U.S. patent number 8,420,632 [Application Number 13/381,234] was granted by the patent office on 2013-04-16 for benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics.
This patent grant is currently assigned to Galderma Research & Developlment. The grantee listed for this patent is Sandrine Chambon, Laurent Chantalat, Laurence Clary, Jean-Claude Pascal, Carine Rosignoli, Olivier Roye, Marlene Schuppli. Invention is credited to Sandrine Chambon, Laurent Chantalat, Laurence Clary, Jean-Claude Pascal, Carine Rosignoli, Olivier Roye, Marlene Schuppli.
United States Patent |
8,420,632 |
Clary , et al. |
April 16, 2013 |
Benzenesulfonamide compounds, method for synthesizing same, and use
thereof in medicine as well as in cosmetics
Abstract
Benzenesulfonamide compounds having a structure of formula (I)
are described. Also described, are methods for synthesizing the
compounds and to the use thereof in pharmaceutical compositions for
human or veterinary medicine and in cosmetic compositions.
Inventors: |
Clary; Laurence (La Colle sur
Loup, FR), Chambon; Sandrine (chemin de l'Olivet,
FR), Chantalat; Laurent (Grasse, FR),
Rosignoli; Carine (Mougins le Haut, FR), Roye;
Olivier (Fayence, FR), Pascal; Jean-Claude (Nice,
FR), Schuppli; Marlene (Le Rouret, FR) |
Applicant: |
Name |
City |
State |
Country |
Type |
Clary; Laurence
Chambon; Sandrine
Chantalat; Laurent
Rosignoli; Carine
Roye; Olivier
Pascal; Jean-Claude
Schuppli; Marlene |
La Colle sur Loup
chemin de l'Olivet
Grasse
Mougins le Haut
Fayence
Nice
Le Rouret |
N/A
N/A
N/A
N/A
N/A
N/A
N/A |
FR
FR
FR
FR
FR
FR
FR |
|
|
Assignee: |
Galderma Research &
Developlment (Biot, FR)
|
Family
ID: |
41600633 |
Appl.
No.: |
13/381,234 |
Filed: |
June 28, 2010 |
PCT
Filed: |
June 28, 2010 |
PCT No.: |
PCT/FR2010/051331 |
371(c)(1),(2),(4) Date: |
August 27, 2012 |
PCT
Pub. No.: |
WO2011/001089 |
PCT
Pub. Date: |
January 06, 2011 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20120323006 A1 |
Dec 20, 2012 |
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Foreign Application Priority Data
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|
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Jun 30, 2009 [FR] |
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09 54460 |
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Current U.S.
Class: |
514/218; 544/363;
544/383; 544/373; 544/361; 544/368; 514/255.02; 544/362;
514/253.06 |
Current CPC
Class: |
A61P
19/08 (20180101); C07D 215/14 (20130101); A61K
31/551 (20130101); A61P 9/10 (20180101); A61P
19/02 (20180101); A61P 25/04 (20180101); A61P
33/06 (20180101); A61P 19/00 (20180101); A61P
9/00 (20180101); A61P 3/10 (20180101); A61P
25/08 (20180101); A61P 21/00 (20180101); A61P
35/00 (20180101); A61P 37/06 (20180101); A61P
3/04 (20180101); A61P 7/00 (20180101); A61P
11/00 (20180101); A61P 31/06 (20180101); A61P
31/18 (20180101); A61P 11/06 (20180101); A61P
21/02 (20180101); A61P 25/02 (20180101); C07D
213/56 (20130101); C07D 295/26 (20130101); A61P
25/06 (20180101); A61P 29/00 (20180101); A61P
43/00 (20180101); C07D 213/30 (20130101); A61P
25/16 (20180101); A61K 31/4965 (20130101); C07D
209/12 (20130101); C07D 261/20 (20130101); A61P
25/00 (20180101); C07D 209/26 (20130101); A61P
37/08 (20180101); C07D 209/24 (20130101); A61P
25/14 (20180101); C07D 295/15 (20130101); C07D
471/04 (20130101); A61K 31/497 (20130101); A61P
17/00 (20180101); A61P 25/28 (20180101); A61P
27/02 (20180101); A61P 17/06 (20180101); C07D
213/55 (20130101); A61P 1/04 (20180101); A61P
31/04 (20180101); C07D 213/68 (20130101); C07D
209/10 (20130101); C07D 209/20 (20130101); Y02A
50/30 (20180101) |
Current International
Class: |
A61K
31/551 (20060101); A61K 31/4965 (20060101); A61K
31/497 (20060101); C07D 295/26 (20060101); C07D
471/04 (20060101); C07D 401/12 (20060101); C07D
413/12 (20060101); C07D 403/12 (20060101) |
Field of
Search: |
;544/363,383,376,360,362 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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WO 2008/045671 |
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Apr 2008 |
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WO |
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Other References
Cancer [online], [retrieved on Jul. 6, 2007] Retrieved from the
Internet, URL: http://www.nlm.nih.gov/medlineplus/cancer.html.
cited by examiner .
Lala et al., Role of nitric oxide in tumor progression: Lessons
from experimental tumors, Cancer and Metastasis Reviews (1998), 17,
91-106. cited by examiner .
Golub et al., Molecular Classification of Cancer: Class Discovery
and Class Prediction by Gene Expression Monitoring, Science (1999),
vol. 286, 531-537. cited by examiner .
International Search Report (PCT/ISA/210) issued on Oct. 28, 2010,
by French Patent Office as the International Searching Authority
for International Application No. PCT/FR2010/051331. cited by
applicant .
Written Opinion of the International Searching Authority (Form
PCT/ISA/237) issued in PCT/FR2010/051331 on Jan. 17, 2012, and an
English language translation of the Written Opinion. cited by
applicant .
Lohmander et al., "The Structure of Aggrecan Fragments in Human
Synovial Fluid," Arthritis & Rheumatism, Sep. 1993, pp.
1214-1222, vol. 36, No. 9, American College of Rheumatology, US.
cited by applicant .
Schlondorff et al., "Intracellular maturation and localization of
the tumor necrosis factor .alpha. convertase (TACE)," Biochem. J.,
2000, pp. 131-138, vol. 347, Biochemical Society, UK. cited by
applicant .
Black et al., "A metalloproteinase disintegrin that releases
tumour-necrosis factor-.alpha. from cells," Nature, Feb. 20, 1997,
pp. 729-733, vol. 385, Nature Publishing Group, UK. cited by
applicant .
Moss et al., "Cloning of a disintegrin metalloproteinase that
processes precursor tumour-necrosis factor-.alpha.," Nature, Feb.
20, 1997, pp. 733-736, vol. 385, Nature Publishing Group, UK. cited
by applicant .
Tamura et al., "Highly Selective and Orally Active Inhibitors of
Type IV Collagenase (MNP-9 and MMP-2): N-Sulfonylamino Acid
Derivatives," J. Med. Chem., 1998, pp. 640-649, vol. 41, American
Chemical Society, US. cited by applicant .
MacPherson et al., "Discovery of CGS 27023A, a Non-Peptidic,
Potent, and Orally Active Stromelysin Inhibitor That Blocks
Cartilage Degradation in Rabbits," J. Med. Chem., 1997, pp.
2525-2532, vol. 40, American Chemical Society, US. cited by
applicant .
Kupper, "Immunologic Targets in Psoriasis," The New England Journal
of Medicine, Nov. 20, 2003, pp. 1987-1990, vol. 349, Issue 21,
Massachusetts Medical Society, US. cited by applicant .
Bonifati et al., "Correlated increases of tumor necrosis
factor-.alpha., interleukin-6 and granulocyte monocyte-colony
stimulating factor levels in suction blister fluids and sera of
psoriatic patients-relationships with disease severity," Chemical
and Experimental Dermatology, 1994, pp. 383-387, vol. 19,
Wiley-Blackwell, UK. cited by applicant .
MacDonald et al., "Tumour necrosis factor-alpha and
interferon-gamma production measured at the single cell level in
normal and inflamed human intestine," Clin. exp. Immunol., 1990,
pp. 301-305, vol. 81, Blackwell Publishing, UK. cited by applicant
.
Elliot et al., "Randomised double-blind comparison of chimeric
monoclonal antibody to tumour necrosis factor .alpha. (cA2) versus
placebo in rheumatoid arthritis," The Lancet, Oct. 22, 1994, pp.
1105-1110, vol. 344, Elservier, UK. cited by applicant.
|
Primary Examiner: Bianchi; Kristin
Attorney, Agent or Firm: SNR Denton US LLP
Claims
The invention claimed is:
1. A compound of formula (I) below: ##STR00009## in which: R.sub.1
represents a hydrogen, an alkyl radical, a substituted alkyl
radical, an alkenyl radical, a substituted alkenyl radical, an
alkynyl radical, a substituted alkynyl radical, an aralkyl radical,
a substituted aralkyl radical, a heteroaralkyl radical, a
substituted heteroaralkyl radical, a --C(O)--R.sub.4 radical, a
--SO.sub.2--R.sub.4 radical, or a C(O)OR.sub.4 radical, with
R.sub.4 having the meanings given hereinafter; R.sub.2 is a
hydrogen atom or a lower alkyl radical; R.sub.3 is an alkyl
radical, a substituted alkyl radical, an alkenyl radical, a
substituted alkenyl radical, an alkynyl radical, a substituted
alkynyl radical, an aryl radical, a substituted aryl radical, an
aralkyl radical, a substituted aralkyl radical, a heterocyclic
radical, a substituted heterocyclic radical, a cycloalkyl radical,
a substituted cycloalkyl radical, a heteroaryl radical, a
substituted heteroaryl radical, a heteroaralkyl radical, or a
substituted heteroaralkyl radical; R.sub.4 is an alkyl radical, a
substituted alkyl radical, an alkenyl radical, a substituted
alkenyl radical, an alkynyl radical, a substituted alkynyl radical,
an aryl radical, a substituted aryl radical, an aralkyl radical, or
a substituted aralkyl radical ; and, n can take the values of 0, 1,
2 or 3; and also addition salts of said compound of formula (I)
with a pharmaceutically acceptable acid, addition salts of said
compound of formula (I) with a pharmaceutically acceptable base,
and enantiomers of said compound of formula (I).
2. The addition salts of the compound as claimed in claim 1, with a
pharmaceutically acceptable acid, wherein the pharmaceutically
acceptable acid is selected from the group consisting of
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, acetic acid, trifluoroacetic acid, trichloroacetic
acid, propionic acid, glycolic acid, pyruvic acid, succinic acid,
benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,
para-toluenesulfonic acid, salicylic acid, picric acid, citric
acid, oxalic acid, tartaric acid, malonic acid, maleic acid,
camphorsulfonic acid, and fumaric acid.
3. The addition salts of the compound as claimed in claim 1, with a
pharmaceutically acceptable base, wherein the pharmaceutically
acceptable base is selected from the group consisting of potassium
hydroxide, sodium hydroxide, lithium hydroxide, calcium hydroxide,
methylamine, ethylamine, ethanolamine, propylamine, isopropylamine,
the 4 isomers of butylamine, dimethylamine, diethylamine,
diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine,
pyrrolidine, piperidine, morpholine, diethanolphenylamine,
trimethylamine, triethylamine, tripropylamine, quinuclidine,
pyridine, quinoline, isoquinoline, lysine, arginine, and
ornithine.
4. The compound as claimed in claim 1, wherein R.sub.1 represents a
hydrogen, an alkyl radical, a substituted alkyl radical, an alkenyl
radical, a substituted alkenyl radical, an alkynyl radical, a
substituted alkynyl radical, an aralkyl radical, a substituted
aralkyl radical, a heteroaralkyl radical, a substituted
heteroaralkyl radical, a --C(O)--R.sub.4 radical, a
--SO.sub.2--R.sub.4 radical, or a C(O)OR.sub.4 radical, with
R.sub.4 having the meanings given hereinafter; R.sub.2 is a
hydrogen atom or a lower alkyl radical; R.sub.3 is an aryl radical,
a substituted aryl radical, an aralkyl radical, a substituted
aralkyl radical, a heterocyclic radical, a substituted heterocyclic
radical, a heteroaryl radical, a substituted heteroaryl radical, a
heteroaralkyl radical, or a substituted heteroaralkyl radical;
R.sub.4 is an alkyl radical, a substituted alkyl radical, an
alkenyl radical, a substituted alkenyl radical, an alkynyl radical,
a substituted alkynyl radical, an aryl radical, a substituted aryl
radical, an aralkyl radical, or a substituted aralkyl radical; and,
n can take the values of 0, 1, or 2; and also addition salts of
said compound with a pharmaceutically acceptable acid, addition
salts of said compound with a pharmaceutically acceptable base, and
enantiomers of said compound.
5. The compound as claimed in claim 1, wherein R.sub.1 represents a
hydrogen, an alkyl radical, a substituted alkyl radical, an alkenyl
radical, a substituted alkenyl radical, an alkynyl radical, a
substituted alkynyl radical, an aralkyl radical, a substituted
aralkyl radical, a --C(O)--R.sub.4 radical, or a
--SO.sub.2--R.sub.4 radical, with R.sub.4 having the meanings given
hereinafter; R.sub.2 is a hydrogen atom or a lower alkyl radical;
R.sub.3 is an aryl radical, a substituted aryl radical, an aralkyl
radical, a substituted aralkyl radical, a heterocyclic radical, a
substituted heterocyclic radical, a heteroaryl radical, a
substituted heteroaryl radical, a heteroaralkyl radical or a
substituted heteroaralkyl radical; R.sub.4 is an alkyl radical, a
substituted alkyl radical, an aryl radical, a substituted aryl
radical, an aralkyl radical, or a substituted aralkyl radical; and,
n can take the values of 1 or 2; and also addition salts of said
compound with a pharmaceutically acceptable acid, addition salts of
said compound with a pharmaceutically acceptable base, and
enantiomers of said compound.
6. The compound as claimed in claim 1, wherein R.sub.1 represents
an alkyl radical, a substituted alkyl radical, an aralkyl radical,
a substituted aralkyl radical, a --C(O)--R.sub.4 radical, or a
--SO.sub.2--R.sub.4 radical, with R.sub.4 having the meanings given
hereinafter; R.sub.2 is a hydrogen atom; R.sub.3 is an aryl
radical, a substituted aryl radical, an aralkyl radical, a
substituted aralkyl radical, a heterocyclic radical, a substituted
heterocyclic radical, a heteroaryl radical, a substituted
heteroaryl radical, a heteroaralkyl radical, or a substituted
heteroaralkyl radical; R.sub.4 is an alkyl radical, a substituted
alkyl radical, an aryl radical, a substituted aryl radical, an
aralkyl radical, or a substituted aralkyl radical; and, n takes the
value of 1; and also addition salts of said compound with a
pharmaceutically acceptable acid, addition salts of said compound
with a pharmaceutically acceptable base, and enantiomers of said
compound.
7. The compound as claimed in claim 1, wherein R.sub.1 represents
an alkyl radical, a substituted alkyl radical, an aralkyl radical,
a substituted aralkyl radical, a --C(O)--R.sub.4 radical, or a
--SO.sub.2--R.sub.4 radical, with R.sub.4 having the meanings given
hereinafter; R.sub.2 is a hydrogen atom; R.sub.3 is a heterocyclic
radical, a substituted heterocyclic radical, a heteroaryl radical,
a substituted heteroaryl radical, a heteroaralkyl radical, or a
substituted heteroaralkyl radical; R.sub.4 is an alkyl radical, a
substituted alkyl radical, an aryl radical, a substituted aryl
radical, an aralkyl radical or a substituted aralkyl radical; and,
n takes the value of 1; and also addition salts of said compound
with a pharmaceutically acceptable acid, addition salts of said
compound with a pharmaceutically acceptable base, and enantiomers
of said compound.
8. The compound as claimed in claim 1, wherein R.sub.1 represents
an alkyl radical, a substituted alkyl radical, an aralkyl radical,
a substituted aralkyl radical, a --C(O)--R.sub.4 radical, or a
--SO.sub.2--1R.sub.4 radical, with R.sub.4 having the meanings
given hereinafter; R.sub.2 is a hydrogen atom; R.sub.3 is a
heteroaryl radical or a substituted heteroaryl radical; R.sub.4 is
an alkyl radical, a substituted alkyl radical, an aryl radical, a
substituted aryl radical, an aralkyl radical, or a substituted
aralkyl radical; and, n takes the value of 1; and also addition
salts of said compound with a pharmaceutically acceptable acid,
addition salts of said compound with a pharmaceutically acceptable
base, and enantiomers of said compound.
9. The compound as claimed in claim 1, wherein the compound is
selected from the group consisting of: 1)
3-[(4-but-2-ynyloxybenzenesulfonyl)methylamino]-N-hydroxy-2-(4-methanesul-
fonylpiperazin-1-yl)propionamide; 2)
(S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-N-hydroxy-2-(4-methanesulfony-
lpiperazin-1-yl)propionamide; 3)
(S)-3-(4-benzyloxybenzenesulfonylamino)-N-hydroxy-2-(4-methanesulfonylpip-
erazin-1-yl)propionamide; 4)
(S)-3-[(4-benzyloxybenzenesulfonyl)methylamino]-N-hydroxy-2-(4-methanesul-
fonylpiperazin-1-yl)propionamide; 5)
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin--
4-ylmethoxy)benzenesulfonylamino]propionamide; 6)
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(naphthalen-1-ylme-
thoxy)benzenesulfonylamino]propionamide; 7)
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzenesulf-
onylamino)propionamide; 8)
(S)-3-[4-(3-cyanobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-(4-methanesu-
lfonylpiperazin-1-yl)propionamide; 9)
(S)-3-[4-(4-cyanobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-(4-methanesu-
lfonylpiperazin-1-yl)propionamide; 10) benzyl
4-{(S)-1-hydroxycarbamoyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfo-
nylamino]ethyl}piperazine-1-carboxylate; 11)
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin-4-
-ylmethoxy)benzenesulfonylamino]propionamide; 12)
(R)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin--
4-ylmethoxy)benzenesulfonylamino]propionamide; 13)
(S)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2--
piperazin-1-yl-propionamide; 14)
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin--
4-ylmethoxy)benzenesulfonylamino]propionamide hydrochloride; 15)
tert-butyl
3-{4-[(S)-2-hydroxycarbamoyl-2-(4-methanesulfonylpiperazin-1-yl)ethylsulf-
amoyl]phenoxymethyl}-2-methylindole-1-carboxylate
di(trifluoroacetate); 16)
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-yl-
methoxy)benzenesulfonylamino]propionamide; 17)
(S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmetho-
xy)benzenesulfonylamino]propionamide; 18)
(S)-2-[4-(4-fluorobenzyl)piperazin-1-yl]-N-hydroxy-3-[4-(2-methylquinolin-
-4-ylmethoxy)benzenesulfonylamino]propionamide; 19)
(S)-2-(4-ethylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethox-
y)benzenesulfonylamino]propionamide; 20)
(S)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2--
[4-(4-trifluoromethyl-benzyl)piperazin-1-yl]propionamide; 21)
(S)-N-hydroxy-2-[4-(4-methylbenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-
-4-ylmethoxy)benzenesulfonylamino]propionamide; 22)
(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-N-hydroxy-2-(4--
methanesulfonylpiperazin-1-yl)propionamide; 23)
(S)-N-hydroxy-2-(4-isobutyrylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylm-
ethoxy)benzenesulfonylamino]propionamide; 24)
(S)-N-hydroxy-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-l]-3-[4-(2-met-
hylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide; 25)
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-trifluoromethyl-
pyrazolo[1,5-a]pyridin-3-ylmethoxy)benzenesulfonylamino]propionamide;
26)
(S)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2--
[4-(propane-2-sulfonyl)piperazin-1-yl]propionamide; 27)
(S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy
-3-[4-(2-trifluoromethylpyrazolo[1,5-a]pyridin-3-ylmethoxy)benzenesulfony-
lamino]propionamide; 28)
(S)-2-(4-acetylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmetho-
xy)benzenesulfonylamino]propionamide; 29)
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-{propyl-[4-(quinolin--
4-ylmethoxy)benzenesulfonyl]amino}propionamide; 30)
(S)-2-(4-benzenesulfonylpiperazin-1-yl)-N-hydroxy-3-[4-(pyrazolo[1,5-a]py-
ridin-3-ylmethoxy)benzenesulfonylamino]propionamide; 31)
(S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(1-methylpiperidin-4-ylmeth-
oxy)benzenesulfonylamino]propionamide; 32)
(S)-2-[4-(4-fluorobenzoyl)piperazin-1-yl]-N-hydroxy-3-[4-(3-m-tolyl-propo-
xy) benzenesulfonylamino]propionamide; 33)
(S)-N-hydroxy-3-[4-(2-methylnaphthalen-1-ylmethoxy)benzenesulfonylamino]--
2-(4-propionylpiperazin-1-yl)propionamide; 34)
(S)-N-hydroxy-3-[4-(4-methylpentyloxy)benzenesulfonylamino]-2-(4-phenylac-
etylpiperazin-1-yl)propionamide; 35)
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3[4-(2-methylpyridin-4--
ylmethoxy)benzenesulfonylamino]propionamide; 36)
(S)-2-(3-acetylimidazolidin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylme-
thoxy)benzenesulfonylamino]propionamide; 37)
(S)-3-[4-(3,5-dimethylbenzyloxy)benzenesulfonylamino]-N-hydroxy-2-imidazo-
lidin-1-yl-propionamide; 38)
(S)-N-hydroxy-2-(4-methanesulfonyl-[1,4]diazepan-1-yl)-3-[4-(2-methylquin-
olin-4-ylmethoxy)benzenesulfonylamino]propionamide; 39)
(S)-2-(4-benzyl-[1,4]diazepan-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-yl-
methoxy)benzenesulfonylamino]propionamide; 40)
(S)-2-[1,4]diazocan-1-yl-N-hydroxy-3-[4-(2-methylguinolin-4-ylmethoxy)ben-
zenesulfonylamino]propionamide.; 41)
(S)-N-hydroxy-3-[4-(2-methylbenzofuran-3-ylmethoxy)benzenesulfonylamino]--
2-[4-(propane-2-sulfonyl)piperazin-1-yl]propionamide; and
42)(S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-isopropyl-1H-indol-3--
ylmethoxy)benzenesulfonylamino]propionamide.
10. A medicament comprising the compound as claimed in claim 1,
addition salts of said compound with a pharmaceutically acceptable
acid, addition salts of said compound with a pharmaceutically
acceptable base, or enantiomers of said compound.
11. The compound as claimed in claim 1, wherein the compound is an
inhibitor of TNF.alpha. production.
12. The compound as claimed in claim 1, wherein the compound is an
inhibitor of TNF.alpha.-converting enzyme (TACE).
13. The medicament of claim 10, wherein the medicament is used for
the treatment of rheumatoid arthritis, non-insulin dependent
diabetes mellitus, Crohn's disease, or psoriasis.
14. A composition comprising the compound as claimed in claim 1,
addition salts of said compound with a pharmaceutically acceptable
acid, addition salts of said compound with a pharmaceutically
acceptable base, or enantiomers of said compound, and a
carrier.
15. The composition of claim 14, wherein the composition is a
pharmaceutical composition.
16. The composition of claim 14, wherein the composition is a
cosmetic composition.
17. A method of treating a disease, comprising administering the
composition of claim 14 to a subject, wherein the disease is
selected from the group consisting of rheumatoid arthritis,
non-insulin dependent diabetes mellitus, Crohn's disease, and
psoriasis.
18. The method of claim 17, wherein the subject is a human or an
animal.
19. A method of inhibiting the activity of TACE, comprising
contacting a TACE with the composition of claim 14.
20. The method of claim 19, wherein the TACE is in a subject.
21. A method of inhibiting the production of TNF.alpha., comprising
administering the composition of claim 14 to a subject.
Description
This application is the United States national phase of
PCT/FR2010/051331, filed Jun. 28, 2010, and designating the United
States (published in the French language on Jan. 6, 2011, as WO
2011/001089 A1; the title and abstract were also published in
English), which claims foreign priority under 35 U.S.C. .sctn.119
of FR 0954460, filed Jun. 30, 2009, each hereby expressly
incorporated by reference in its entirety and each assigned to the
assignee hereof.
TECHNICAL FIELD
The present invention relates to novel benzenesulfonamide compounds
corresponding to general formula (I) below:
##STR00001## and also to the process for synthesizing same and to
the use thereof in pharmaceutical compositions intended for use in
human or veterinary medicine.
The compounds of the present invention act as inhibitors of
TNF.alpha.-converting enzyme, also known as TACE. They are
consequently of use in the treatment of diseases for which reducing
TNF.alpha. production is of great interest.
The present invention also relates to the use of the compounds
corresponding to general formula (I) in cosmetic compositions.
PRIOR ART
Adamalysins ("ADAM" or A Disintegrin and Metalloproteinase) are a
subfamily of zinc metalloendopeptidase enzymes. Their ectodomain
comprises a protease domain, the activation of which is
zinc-dependent, a disintegrin domain and a cysteine-rich domain. To
date, at least 30 different ADAMs have been identified, of which
the first characterized was ADAM17, also known as TACE
(TNF.alpha.-converting enzyme) [Gueydan C et al. Med. Sci 1997, 13,
83-88; Black R. A et al. Nature 1997, 385:729-733; Moss et al.
Nature 1997, 385:733-736]. The TACE mRNA is present in many tissues
and more particularly in monocytes, macrophages and T lymphocytes,
but also in keratinocytes for example.
TACE is responsible for the cleavage of pro-TNF.alpha., a 26 kDa
membrane protein, so as to result in the release of biologically
active soluble TNF.alpha., a 17 kDa protein [Schlondorff et al.
Biochem. J. 2000, 347, 131-138]. The soluble TNF.alpha. released by
the cell is capable of acting on sites very remote from the site of
synthesis.
TNF.alpha. is involved in a large number of pro-inflammatory
biological processes [Aggarwal et al, Eur. Cytokine Netw., 1996, 7:
93-124]. Several pharmacological and clinical studies have shown in
an obvious manner that blocking the effects of TNF.alpha. with
specific anti-TNF.alpha. antibodies or anti-TNF.alpha. biologicals
(Etanercept, Adalimumab, Infliximab) is beneficial in the treatment
of autoimmune diseases such as rheumatoid arthritis [Feldman et al.
Lancet, 1994, 344, 1105], non-insulin-dependent diabetes mellitus
[Lohmander L. S et al. Arthritis Rheum, 1993, 36, 1214-1222], or
Crohn's disease [MacDonald et al. Clin. Exp. Immunol. 1990, 81,
301].
TNF.alpha. also plays a fundamental role during the inflammantory
phenomenon triggered in psoriasis lesions. Serum TNF.alpha. levels
are elevated in psoriatic patients [Mussi A et al. J. Biol. Regul.
Homeost Agents, 1997, 11, 115-118]; TNF.alpha. levels are also
elevated in the actual psoriasis plaques [Bonifati C. et al. Clin.
Exp. Dermatol., 1994, 19, 383-387]. The key cells in the
physiopathology of psoriasis are keratinocytes, dendritic cells and
certain T lymphocytes. The interaction between these families of
cells results in an inflammatory cascade that leads to the
characteristic psoriasis lesions with release of TNF.alpha. [Kupper
TS, N. Engl. J. Med, 2003, 349, 1987-1990]. Clinical studies for
the treatment of moderate to severe plaque psoriasis with
anti-TNF.alpha. biologicals (Etanercept, Adalimumab, Infliximab)
have demonstrated their efficacy both on psoriasis lesions and on
the quality of life of the patients [Ortonne J P, Annales de
dermatologie et de venereologie {Annals of dermatology and
venereology], 2005, 132 (8-9 pt2), 4S6-9 and 2005, 132,
9S01-9S70].
Thus, compounds which inhibit TNF.alpha. production are of great
interest for the treatment of inflammatory diseases and diseases
involving TNF.alpha. release.
SUMMARY OF THE INVENTION
Our invention therefore describes novel molecules which inhibit the
TACE enzyme (TNF.alpha.-converting enzyme) and, as a result,
inhibit the secretion of soluble TNF.alpha. (active form of
TNF.alpha.) by cells. These novel molecules are therefore potential
active ingredients for the treatment of pathological conditions
which involves a decrease or an inhibition of TNF.alpha.
production.
By way of illustration, and in a nonlimiting manner, these
pathological conditions are, for example, septic shock, hemodynamic
shock, malaria, inflammatory bowel diseaases (IBDs) such as Crohn's
disease and ulcerative colitis, inflammatory bone diseases,
mycobacterial infections, meningitis, fibrotic diseases, cardiac
diseases, ischemic attack, transplant rejection, cancer,
atherosclerosis, obesity, diseases involving angiogenesis
phenomena, autoimmune diseases, osteoarthritis, rheumatoid
arthritis, ankylosing spondylitis, juvenile chronic arthritis,
multiple sclerosis, HIV, non-insulin-dependent diabetes mellitus,
allergic diseases, asthma, chronic obstructive pulmonary disease
(COPD), occular inflammation, inflammatory skin diseases,
psoriasis, atopic dermatitis and psoriatic arthritis.
These molecules are also potential active ingredients for the
treatment of neurological pathological conditions that are
inflammatory in nature, for which reducing TNF.alpha. production
would be of great interest. These pathological conditions listed
hereinafter in a nonlimiting manner are, for example, Alzheimer's
disease, Parkinson's disease, parkinsonian disorders, amyotrophic
lateral sclerosis, autoimmune diseases of the nervous system,
autonomic diseases of the nervous system, dorsal pain, cerebral
edema, cerebrovascular disorders, dementia, nervous system nerve
fiber demyelinating autoimmune diseases, diabetic neuropathies,
encephalitis, encephalomyelitis, epilepsy, chronic fatigue
syndrome, giant cell arteritis, Guillain-Barre syndrome, headaches,
multiple sclerosis, neuralgia, peripheral nervous system diseases,
polyneuropathies, polyradiculoneuropathy, radiculopathy,
respiratory paralysis, spinal cord diseases, Tourette's syndrome,
central nervous system vasculitis, Huntington's disease and
stroke.
A large variety of TACE inhibitors is already known as indicated
below. However, a large number of these inhibitors do not act
selectively on the TACE enzyme compared with other enzymes of the
family of ADAMs and/or of matrix metalloproteinases (MMPs).
As it happens, the nonselective inhibition of these enzyme families
induces adverse side effects observed in vivo. For example, the
inhibition of MMP-1 (collagenase-1) has been associated with
musculoskeletal toxicity problems.
As a nonselective inhibitor, mention may also be made of
Apratastat, a known inhibitor tested clinically in phase 2 for the
treatment of rheumatoid arthritis (Curr Opin Investig Drugs. 2006
November; 7(11), 1014-1019). This inhibitor is not selective for
the TACE enzyme compared with certain MMPs (WO 00/44709; page 251,
table 10, example 61).
Other TACE inhibitors which are also known and are part of the same
family as Apratastat, namely that of cyclic benzenesulfonamide
derivatives, have been described in WO 00/44709 and WO 97/18194.
Other patents (WO 96/00214, WO 97/22587) claim MMP and/or TACE
inhibitors for which the benzenesulfonamide part is separated from
the hydroxamic acid function by a single carbon atom. Publications
describing MMP inhibitors of this type more broadly are also the
publication by MacPherson et al. J. Med. Chem. 1997, 40, 2525 and
the publication by Tamura et al. J. Med. Chem. 1998, 41, 640. Other
examples of MMP/TACE inhibitors for which the sulfonamide function
is separated from the hydroxamic acid by a series of two carbon
atoms forming a ring are described in patents WO 98/16503, WO
98/16506, WO 98/16514 and WO 98/16520. Other examples of MMP
inhibitors for which the sulfonamide function is separated from the
hydroxamic acid by a series of two carbon atoms are also described
in WO 2008/045671.
As it happens, the applicant has now discovered, unexpectedly and
surprisingly, that novel compounds of general formula (I) exhibit a
very good TACE-inhibiting activity, and in particular inhibit the
TACE enzyme selectively compared with other ADAMs and MMPs.
Thus, the present invention relates to compounds of general formula
(I) below:
##STR00002## in which: R.sub.1 represents a hydrogen, an alkyl
radical, a substituted alkyl radical, an alkenyl radical, a
substituted alkenyl radical, an alkynyl radical, a substituted
alkynyl radical, an aralkyl radical, a substituted aralkyl radical,
a heteroaralkyl radical, a substituted heteroaralkyl radical, a
--C(O)--R.sub.4 radical, an --SO.sub.2--R.sub.4 radical, or a
C(O)OR.sub.4 radical, R.sub.4 having the meanings given
hereinafter; R.sub.2 is a hydrogen atom or a lower alkyl radical;
R.sub.3 is an alkyl radical, a substituted alkyl radical, an
alkenyl radical, a substituted alkenyl radical, an alkynyl radical,
a substituted alkynyl radical, an aryl radical, a substituted aryl
radical, an aralkyl radical, a substituted aralkyl radical, a
heterocyclic radical, a substituted heterocyclic radical, a
cycloalkyl radical, a substituted cycloalkyl radical, a heteroaryl
radical, a substituted heteroaryl radical, a heteroaralkyl radical
or a substituted heteroaralkyl radical; R.sub.4 is an alkyl
radical, a substituted alkyl radical, an alkenyl radical, a
substituted alkenyl radical, an alkynyl radical, a substituted
alkynyl radical, an aryl radical, a substituted aryl radical, an
aralkyl radical or a substituted aralkyl radical; n can take the
values of 0, 1, 2 or 3; and also the addition salts of the
compounds of general formula (I) with a pharmaceutically acceptable
acid, the addition salts of the compounds of general formula (I)
with a pharmaceutically acceptable base, and the enantiomers of the
compounds of general formula (I).
Among the addition salts of the compounds of general formula (I)
with a pharmaceutically acceptable acid, mention may preferably be
made of the salts with an organic acid or with an inorganic acid.
The suitable inorganic acids are, for example, hydrohalic acids
such as hydrochloric acid or hydrobromic acid, sulfuric acid,
nitric acid and phosphoric acid.
The suitable organic acids are, for example, acetic acid,
trifluoroacetic acid, trichloroacetic acid, propionic acid,
glycolic acid, pyruvic acid, succinic acid, benzoic acid, cinnamic
acid, mandelic acid, methanesulfonic acid, para-toluenesulfonic
acid, salicylic acid, picric acid, citric acid, oxalic acid,
tartaric acid, malonic acid, maleic acid, camphorsulfonic acid and
fumaric acid.
Among the addition salts of the compounds of general formula (I)
with a pharmaceutically acceptable base, mention may preferably be
made of the salts with an organic base or with an inorganic base.
The inorganic bases are, for example, potassium hydroxide, sodium
hydroxide, lithium hydroxide or calcium hydroxide.
The suitable organic bases comprise amines and amino acids. Among
the amines, mention may, for example, be made of aliphatic or
aromatic, primary, secondary or tertiary amines, such as
methylamine, ethylamine, ethanolamine, propylamine, isopropylamine,
the 4 isomers of butylamine, dimethylamine, diethylamine,
diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine,
pyrrolidine, piperidine, morpholine, diethanolphenylamine,
trimethylamine, triethylamine, tripropylamine, quinuclidine,
pyridine, quinoline or isoquinoline.
Among the amino acids, mention may, for example, be made of lysine,
arginine and ornithine.
According to the present invention, the term "lower alkyl radical"
denotes a linear or branched, saturated hydrocarbon-based chain
containing from 1 to 4 carbon atoms.
According to the present invention, the term "alkyl radical"
denotes a linear or branched, saturated hydrocarbon-based chain
containing from 1 to 10 carbon atoms.
According to the present invention, the term "alkenyl radical"
denotes a linear or branched, unsaturated hydrocarbon-based chain
containing from 2 to 10 carbon atoms and comprising one or more
double bonds.
According to the present invention, the term "alkynyl radical"
denotes a linear or branched, unsaturated hydrocarbon-based chain
containing from 2 to 10 carbon atoms and comprising one or more
triple bonds.
According to the present invention, the term "substituted alkyl
radical" denotes a linear or branched, saturated hydrocarbon-based
chain containing from 1 to 10 carbon atoms and substituted with one
or more radicals chosen from a halogen atom, an alkoxy radical and
a hydroxyl radical.
According to the present invention, the term "substituted alkenyl
radical" denotes a linear or branched, unsaturated
hydrocarbon-based chain containing from 2 to 10 carbon atoms,
comprising one or more double bonds and substituted with one or
more radicals chosen from a halogen atom, an alkoxy radical and a
hydroxyl radical.
According to the present invention, the term "substituted alkynyl
radical" denotes a linear or branched, unsaturated
hydrocarbon-based chain containing from 2 to 10 carbon atoms,
comprising one or more triple bonds and substituted with one or
more radicals chosen from a halogen atom, an alkoxy radical and a
hydroxyl radical.
According to the present invention, the term "cycloalkyl" denotes a
cyclic saturated hydrocarbon-based chain containing from 3 to 7
carbon atoms.
According to the present invention, the term "substituted
cycloalkyl" denotes a cyclic saturated hydrocarbon-based chain
containing from 3 to 7 carbon atoms and substituted with one or
more radicals chosen from a halogen atom, an alkoxy radical and a
hydroxyl radical.
According to the present invention, the term "aryl radical" denotes
an aromatic hydrocarbon-based ring or two fused aromatic
hydrocarbon-based rings.
The preferred aryl radicals are chosen from phenyl and naphthyl
radicals.
According to the present invention, the term "substituted aryl
radical" denotes an aromatic hydrocarbon-based ring or two fused
aromatic hydrocarbon-based rings which is (are) substituted with
one or more groups of atoms chosen from an alkyl, an alkoxy, an
aryl, a halogen, a hydroxyl, a cyano, a trifluoromethyl and a
nitro.
According to the present invention, the term "aralkyl radical"
denotes an alkyl substituted with an aryl.
According to the present invention, the term "substituted aralkyl
radical" denotes an alkyl substituted with a substituted aryl.
According to the present invention, the term "heterocyclic radical"
denotes a saturated or unsaturated, cyclic or polycyclic
hydrocarbon-based chain comprising one or more heteroatoms chosen
from O, S and N.
According to the present invention, the term "substituted
heterocyclic radical" denotes a heterocyclic radical substituted
with one or more groups of atoms chosen from an alkyl, an alkoxy, a
halogen, a hydroxyl, a cyano, a trifluoromethyl and a nitro.
According to the present invention, the term "heteroaryl radical"
denotes an aromatic heterocyclic radical, i.e. a cyclic or
polycyclic aromatic hydrocarbon-based chain, comprising one or more
heteroatoms chosen from O, S and N.
According to the present invention, the term "substituted
heteroaryl radical" denotes a heteroaryl radical substituted with
one or more groups of atoms chosen, for example, from an alkyl, an
alkoxy, an aryl, a substituted aryl, a halogen, a hydroxyl, a
cyano, a trifluoromethyl and a nitro.
According to the present invention, the term "heteroaralkyl
radical" denotes an alkyl radical substituted with a heteroaryl
radical.
According to the present invention, the term "substituted
heteroaralkyl radical" denotes a heteroaralkyl radical substituted
with one or more groups of atoms chosen from an alkyl, an alkoxy, a
halogen, a hydroxyl, a cyano, a trifluoromethyl and a nitro.
According to the present invention, the term "alkoxy radical"
denotes an oxygen atom substituted with an alkyl radical.
According to the present invention, the term "halogen atom" denotes
a fluorine, chlorine, bromine or iodine atom.
Among the compounds of general formula (I) which fall within the
context of the present invention, mention may in particular be made
of the following compounds: 1)
3-[(4-but-2-ynyloxybenzenesulfonyl)methylamino]-N-hydroxy-2-(4-methanesul-
fonylpiperazin-1-yl)propionamide 2)
(S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-N-hydroxy-2-(4-methanesulfony-
lpiperazin-1-yl)propionamide 3)
(S)-3-(4-benzyloxybenzenesulfonylamino)-N-hydroxy-2-(4-methanesulfonylpip-
erazin-1-yl)propionamide 4)
(S)-3-[(4-benzyloxybenzenesulfonyl)methylamino]-N-hydroxy-2-(4-methanesul-
fonylpiperazin-1-yl)propionamide 5)
(S)--N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-
-4-ylmethoxy)benzenesulfonylamino]propionamide 6)
(S)--N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(naphthalen-1-ylm-
ethoxy)benzenesulfonylamino]propionamide 7)
(S)--N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzenesul-
fonylamino)propionamide 8)
(S)-3-[4-(3-cyanobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-(4-methanesu-
lfonylpiperazin-1-yl)propionamide 9)
(S)-3-[4-(4-cyanobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-(4-methanesu-
lfonylpiperazin-1-yl)propionamide 10) benzyl
4-{(S)-1-hydroxycarbamoyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfo-
nylamino]ethyl}piperazine-1-carboxylate 11)
(S)--N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin--
4-ylmethoxy)benzenesulfonylamino]propionamide 12)
(R)--N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-
-4-ylmethoxy)benzenesulfonylamino]propionamide 13)
(S)--N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-
-piperazin-1-yl-propionamide 14)
(S)--N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-
-4-ylmethoxy)benzenesulfonylamino]propionamide hydrochloride 15)
tert-butyl
3-{(4-[(S)-2-hydroxycarbamoyl-2-(4-methanesulfonylpiperazin-1-yl)ethylsul-
famoyl]phenoxymethyl}-2-methylindole-1-carboxylate
di(trifluoroacetate) 16)
(S)--N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-y-
lmethoxy)benzenesulfonylamino]propionamide 17)
(S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmetho-
xy)benzenesulfonylamino]propionamide 18)
(S)-2-[4-(4-fluorobenzyl)piperazin-1-yl]-N-hydroxy-3-[4-(2-methylquinolin-
-4-ylmethoxy)benzenesulfonylamino]propionamide 19)
(S)-2-(4-ethylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethox-
y)benzenesulfonylamino]propionamide 20)
(S)--N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-
-[4-(4-trifluoromethyl-benzyl)piperazin-1-yl]propionamide 21)
(S)--N-hydroxy-2-[4-(4-methylbenzyl)piperazin-1-yl]-3-[4-(2-methylquinoli-
n-4-ylmethoxy)benzenesulfonylamino]propionamide 22)
(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-N-hydroxy-2-(4--
methanesulfonylpiperazin-1-yl)propionamide 23)
(S)--N-hydroxy-2-(4-isobutyrylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-yl-
methoxy)benzenesulfonylamino]propionamide 24)
(S)--N-hydroxy-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-l]-3-[4-(2-me-
thylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide 25)
(S)--N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-trifluoromethy-
lpyrazolo[1,5-a]pyridin-3-ylmethoxy)benzenesulfonylamino]propionamide
26)
(S)--N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-
-[4-(propane-2-sulfonyl)piperazin-1-yl]propionamide 27)
(S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-trifluoromethylpyrazolo[-
1,5-a]pyridin-3-ylmethoxy)benzenesulfonylamino]propionamide 28)
(S)-2-(4-acetylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmetho-
xy)benzenesulfonylamino]propionamide 29)
(S)--N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-{propyl-[4-(quinolin-
-4-ylmethoxy)benzenesulfonyl]amino}propionamide 30)
(S)-2-(4-benzenesulfonylpiperazin-1-yl)-N-hydroxy-3-[4-(pyrazolo[1,5-a]py-
ridin-3-ylmethoxy)benzenesulfonylamino]propionamide 31)
(S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(1-methylpiperidin-4-ylmeth-
oxy)benzenesulfonylamino]propionamide 32)
(S)-2-[4-(4-fluorobenzoyl)piperazin-1-yl]-N-hydroxy-3-[4-(3-m-tolyl-propo-
xy)benzenesulfonylamino]propionamide 33)
(S)--N-hydroxy-3-[4-(2-methylnaphthalen-1-ylmethoxy)benzenesulfonylamino]-
-2-(4-propionylpiperazin-1-yl)propionamide 34)
(S)--N-hydroxy-3-[4-(4-methylpentyloxy)benzenesulfonylamino]-2-(4-phenyla-
cetylpiperazin-1-yl)propionamide 35)
(S)--N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylpyridin--
4-ylmethoxy)benzenesulfonylamino]propionamide 36)
(S)-2-(3-acetylimidazolidin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylme-
thoxy)benzenesulfonylamino]propionamide 37)
(S)-3-[4-(3,5-dimethylbenzyloxy)benzenesulfonylamino]-N-hydroxy-2-imidazo-
lidin-1-yl-propionamide 38)
(S)--N-hydroxy-2-(4-methanesulfonyl-[1,4]diazepan-1-yl)-3-[4-(2-methylqui-
nolin-4-ylmethoxy)benzenesulfonylamino]propionamide 39)
(S)-2-(4-benzyl-[1,4]diazepan-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-yl-
methoxy)benzenesulfonylamino]propionamide 40)
(S)-2-[1,4]diazocan-1-yl-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)ben-
zenesulfonylamino]propionamide. 41)
(S)--N-hydroxy-3-[4-(2-methylbenzofuran-3-ylmethoxy)benzenesulfonylamino]-
-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propionamide
42)(S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-isopropyl-1H-indol-3--
ylmethoxy)benzenesulfonylamino]propionamide
The compounds of general formula (I) are prepared according to the
reaction scheme (Scheme 1) presented below.
##STR00003##
According to Scheme 1, the compounds (3) are obtained by reaction
between the amino acid (1) H-DAP(Boc)-OMe.HCl or
H-(D)-DAP(Boc)-OMe.HCl and the compound (2) (commercial or prepared
beforehand) in the presence of an organic tertiary base such as
diisopropylethylamine or triethylamine at a temperature of between
60.degree. C. and 120.degree. C. The compounds (4) are obtained by
deprotection of the amine function of compounds (3) according to
conventional methods such as, for example, the use of a solution of
hydrochloric acid in isopropanol.
A reaction between the compound (4) and 4-hydroxybenzenesulfonyl
chloride O-protected with a benzyl group for example
(P.dbd.CH.sub.2-Ph) (5) in the presence of a tertiary amine such
as, for example, triethylamine in dichloromethane, produces the
compound (6). An N-alkylation of the sulfonamide function can then
be carried out by reaction with an alkyl halide in the presence of
a base such as, for example, potassium carbonate in a solvent such
as DMF, so as to give the derivative (7). The compound (8) is
obtained by deprotection according to methods known by those
skilled in the art for deprotecting a phenol function. The compound
(9) is obtained by alkylation of the phenol function of the
compound (8) by reaction with an alkyl halide in the presence of a
base such as, for example, cesium carbonate in acetone, or via a
Mitsunobu reaction with a primary alcohol derivative in the
presence of triphenylphosphine and of diisopropyl azodicarboxylate
for example. The compound (10) is obtained via a saponification
reaction in the presence of a base such as lithium hydroxide in the
presence of water and of tetrahydrofuran for example. In a final
step, the compound (11) is obtained by coupling between
O-(tert-butyldimethylsilyl)hydroxylamine for example and the
derivative (10) under conventional peptide coupling conditions,
using, for example, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride, hydroxybenzotriazole or TBTU as coupling agents, and
triethylamine or diisopropylethylamine as base, in a solvent such
as dichloromethane or dimethylformamide. The deprotection of the
silylated hydroxamic acid intermediately formed is carried out in
situ or by washing with a slightly acidic aqueous solution, so as
to give the compound (11).
Another alternative for obtaining the compound (11) is presented in
Scheme 2 below.
##STR00004##
According to the synthesis scheme of Scheme 2, the derivative (3)
can optionally be alkylated in the presence of a base such as
sodium hydride and of an alkyl halide in dimethylformamide, for
example, so as to give the compound (12), from which the compound
(13) is obtained according to conventional methods for deprotecting
amines, for instance the use of a solution of hydrochloric acid in
isopropanol. The compound (14) is prepared beforehand from the
commercially available 4-hydroxybenzenesulfonic acid sodium salt by
alkylation with an alkyl halide in the presence of a base such as
sodium hydroxide, for example, in a mixture of solvents such as
isopropanol and water, for example. The compound (15) is then
obtained by reacting the derivative (14) with oxalyl chloride in
the presence of dimethylformamide in dichloromethane, for
example.
The derivative (9) is obtained by reaction between the compounds
(13) and (15) in the presence of a base such as triethylamine in
dichloromethane, for example.
An alternative synthesis pathway for obtaining the compound (11) is
also presented in Scheme 3 below.
##STR00005## ##STR00006##
According to Scheme 3, the compound (17) is obtained by reaction
between the amino acid (1) H-DAP(Boc)-OMe.HCl or
H-(D)-DAP(Boc)-OMe.HCl and the compound (16) (prepared beforehand
by reacting bis(2-chloroethyl)amine for example and benzyl bromide
in the presence of potassium carbonate in acetonitrile) in the
presence of an organic tertiary base such as diisopropylethylamine
at a temperature of approximately 120.degree. C. After deprotection
of the amine function, the compound (18) is condensed with sulfonyl
chloride (15) so as to give the derivative (19). An N-alkylation of
the sulfonamide function can then be carried out by reaction with
an alkyl halide in the presence of a base such as, for example,
potassium carbonate in a solvent such as DMF, so as to give the
derivative (20). The compound (21) is obtained according to the
conventional conditions for hydrogenation of the compound (20) in
the presence of palladium-on-carbon in a solvent such as ethanol
for example. The compound (9) is obtained according to the
conventional synthesis methods, for example, by reaction of the
compound (21) with an acyl chloride, or a sulfonyl chloride in the
presence of triethylamine, or by reaction with an alkyl halide in
the presence of a base such as sodium hydride, for example. The
compound (10) is obtained via a saponification reaction in the
presence of a base such as lithium hydroxide in the presence of
water and of tetrahydrofuran, for example. In a final step, the
compound (11) is obtained by coupling between
O-(tert-butyldimethylsilyl)hydroxylamine, for example, and the
derivative (10) under conventional peptide coupling conditions,
using, for example, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride, hydroxybenzotriazole or TBTU as coupling agents, and
triethylamine or diisopropylethylamine as base, in a solvent such
as dichloromethane or dimethylformamide. The deprotection of the
silylated hydroxamic acid intermediately formed is carried out in
situ or by washing with an acidic aqueous solution, so as to give
the compound (11).
An alternative synthesis pathway for the compounds with R.sub.1
representing a --(CO)--R.sub.4 radical is described in Scheme
4.
##STR00007## ##STR00008##
After deprotection of the amine function of the compound (17)
according to conventional conditions for hydrogenation in the
presence of palladium-on-carbon in a solvent such as ethanol for
example, the compound (22) is obtained. The compound (23) is
obtained by reaction with an acyl chloride, R.sub.4COCl, in the
presence of a base such as triethylamine. When R.sub.2 represents a
lower alkyl radical, an N-alkylation of the carbamate is then
carried out by reaction with an alkyl halide in the presence of a
base such as, for example, potassium carbonate in a solvent such as
DMF, so as to give the derivative (24). The compound (25) is
prepared via a saponification reaction in the presence of a base
such as lithium hydroxide in the presence of water and of
tetrahydrofuran, for example. Coupling between O-allylhydroxylamine
hydrochloride, for example, and the derivative (25) makes it
possible to obtain the compound (26) under conventional peptide
coupling conditions. For this, use is made, for example, of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,
hydroxybenzotriazole or TBTU as coupling agents, and triethylamine
or diisopropylethylamine as base. The reaction is carried out in a
solvent such as dichloromethane or dimethylformamide. After
deprotection of the amine function of the compound (26) according
to conventional methods, the compound (27) is obtained. It is
condensed with sulfonyl chloride (15) so as to give the compound
(28). In a final step, the compound (29) is obtained by
deprotection of the hydroxylamine function of the compound (28)
according to conventional methods such as, for example, treatment
with tetrakis(triphenylphosphine)palladium(0) and potassium
carbonate in methanol.
According to the present invention, the preferred compounds of
general formula (I) are those for which: R.sub.1 represents a
hydrogen, an alkyl radical, a substituted alkyl radical, an alkenyl
radical, a substituted alkenyl radical, an alkynyl radical, a
substituted alkynyl radical, an aralkyl radical, a substituted
aralkyl radical, a heteroaralkyl radical, a substituted
heteroaralkyl radical, a --C(O)--R.sub.4 radical, an
--SO.sub.2--R.sub.4 radical or a C(O)OR.sub.4 radical, R.sub.4
having the meanings given hereinafter; R.sub.2 is a hydrogen atom
or a a lower alkyl radical; R.sub.3 is an aryl radical, a
substituted aryl radical, an aralkyl radical, a substituted aralkyl
radical, a heterocyclic radical, a substituted heterocyclic
radical, a heteroaryl radical, a substituted heteroaryl radical, a
heteroaralkyl radical or a substituted heteroaralkyl radical;
R.sub.4 is an alkyl radical, a substituted alkyl radical, an
alkenyl radical, a substituted alkenyl radical, an alkynyl radical,
a substituted alkynyl radical, an aryl radical, a substituted aryl
radical, an aralkyl radical or a substituted aralkyl radical; n can
take the values of 0, 1 or 2; and also their addition salts with a
pharmaceutically acceptable acid, their addition salts with a
pharmaceutically acceptable base, and the enantiomers of said
compounds.
According to the present invention, the particularly preferred
compounds of general formula (I) are those for which: R.sub.1
represents a hydrogen, an alkyl radical, a substituted alkyl
radical, an alkenyl radical, a substituted alkenyl radical, an
alkynyl radical, a substituted alkynyl radical, an aralkyl radical,
a substituted aralkyl radical, a --C(O)--R.sub.4 radical or an
--SO.sub.2--R.sub.4 radical, R.sub.4 having the meanings given
hereinafter; R.sub.2 is a hydrogen atom or a lower alkyl radical;
R.sub.3 is an aryl radical, a substituted aryl radical, an aralkyl
radical, a substituted aralkyl radical, a heterocyclic radical, a
substituted heterocyclic radical, a heteroaryl radical, a
substituted heteroaryl radical, a heteroaralkyl radical or a
substituted heteroaralkyl radical; R.sub.4 is an alkyl radical, a
substituted alkyl radical, an aryl radical, a substituted aryl
radical, an aralkyl radical or a substituted aralkyl radical; n can
take the values of 1 or 2; and also their addition salts with a
pharmaceutically acceptable acid, their addition salts with a
pharmaceutically acceptable base, and the enantiomers of said
compounds.
According to the present invention, the more particularly preferred
compounds of general formula (I) are those for which: R.sub.1
represents an alkyl radical, a substituted alkyl radical, an
aralkyl radical, a substituted aralkyl radical, a --C(O)--R.sub.4
radical or an --SO.sub.2--R.sub.4 radical, R.sub.4 having the
meanings given hereinafter; R.sub.2 is a hydrogen atom; R.sub.3 is
an aryl radical, a substituted aryl radical, an aralkyl radical, a
substituted aralkyl radical, a heterocyclic radical, a substituted
heterocyclic radical, a heteroaryl radical, a substituted
heteroaryl radical, a heteroaralkyl radical or a substituted
heteroaralkyl radical; R.sub.4 is an alkyl radical, a substituted
alkyl radical, an aryl radical, a substituted aryl radical, an
aralkyl radical or a substituted aralkyl radical; n takes the value
of 1; and also their addition salts with a pharmaceutically
acceptable acid, their addition salts with a pharmaceutically
acceptable base, and the enantiomers of said compounds.
According to the present invention, the even more particularly
preferred compounds of general formula (I) are those for which:
R.sub.1 represents an alkyl radical, a substituted alkyl radical,
an aralkyl radical, a substituted aralkyl radical, a
--C(O)--R.sub.4 radical or an --SO.sub.2--R.sub.4 radical, R.sub.4
having the meanings given hereinafter; R.sub.2 is a hydrogen atom;
R.sub.3 is a heterocyclic radical, a substituted heterocyclic
radical, a heteroaryl radical, a substituted heteroaryl radical, a
heteroaralkyl radical or a substituted heteroaralkyl radical;
R.sub.4 is an alkyl radical, a substituted alkyl radical, an aryl
radical, a substituted aryl radical, an aralkyl radical or a
substituted aralkyl radical; n takes the value of 1; and also their
addition salts with a pharmaceutically acceptable acid, their
addition salts with a pharmaceutically acceptable base, and the
enantiomers of said compounds.
According to the present invention, the most particularly preferred
compounds of general formula (I) are those for which: R.sub.1
represents an alkyl radical, a substituted alkyl radical, an
aralkyl radical, a substituted aralkyl radical, a --C(O)--R.sub.4
radical or an --SO.sub.2--R.sub.4 radical, R.sub.4 having the
meanings given hereinafter; R.sub.2 is a hydrogen atom; R.sub.3 is
a heteroaryl radical or a substituted heteroaryl radical; R.sub.4
is an alkyl radical, a substituted alkyl radical, an aryl radical,
a substituted aryl radical, an aralkyl radical or a substituted
aralkyl radical; n takes the value of 1; and also their addition
salts with a pharmaceutically acceptable acid, their addition salts
with a pharmaceutically acceptable base, and the enantiomers of
said compounds.
The compounds according to the invention exhibit a very good
TACE-inhibiting activity and, In particular, they inhibit the TACE
enzyme selectively compared with other ADAMs and MMPs. This TACE
enzyme-inhibiting activity is measured in an enzymatic assay and
quantified via the measurement of an IC.sub.50 (inhibitory
concentration necessary to obtain 50% inhibition of the TACE
enzyme), as described in example 28. The compounds of the present
invention have an IC.sub.50 for TACE less than or equal to 10 .mu.M
and more particularly less than or equal to 1 .mu.M.
Advantageously, the compounds of the present invention have an
IC.sub.50 for TACE less than or equal to 0.5 .mu.M. Advantageously,
these compounds are also very selective for TACE compared with the
other ADAMs and MMPs (assay described in example 29): their
inhibitory activity is at least 10 times greater for TACE than for
other ADAMs and MMPs (i.e. the IC.sub.50 value for TACE is at least
10 times smaller than that for other ADAMs and MMPs), and more
advantageously at least 100 times greater.
TACE (TNF.alpha.-converting enzyme) catalyses the formation of
soluble TNF-alpha from the precursor protein (transmembrane
TNF.alpha.) bound to the membranes of certain cells. TNF.alpha. is
a pro-inflammatory cytokine which is known to play a role in many
pathological conditions with an inflammatory nature.
The invention is therefore directed toward the use of at least one
compound of general formula (I) as defined above, for the treatment
of pathological conditions and disorders linked to TNF.alpha.
release. A TACE enzyme inhibitor of general formula (I) decreases
TNF.alpha. production. As a result, it is of use for the treatment
of pathological conditions linked to TNF.alpha. release.
The invention is also directed toward the use of at least one
compound of general formula (I) as defined above, for preparing a
pharmaceutical or cosmetic composition in which said compound has
TACE enzyme-inhibiting activity.
It is therefore directed toward the use of at least one compound of
general formula (I) as defined above, for the treatment of
pathological conditions or disorders which are improved by
inhibiting the TACE enzyme.
The invention also relates to a method of therapeutic (human or
animal) or cosmetic treatment, which consists of the administration
or the application of a pharmaceutical or cosmetic composition
comprising a compound of general formula (I) as a TACE inhibitor
and, consequently, as an inhibitor of soluble TNF.alpha.
production.
Thus, the invention relates to the use of at least one compound of
general formula (I) as defined above, for the treatment of
pathological conditions or disorders linked to TNF.alpha.
production.
The invention also relates to the use of a compound of general
formula (I) as defined above, for preparing a medicament intended
for the treatment of pathological conditions for which reducing
TNF.alpha. production would be of great interest.
Indeed, the compounds used according to the invention are
particularly suitable for the treatment and prevention of
disorders/diseases such as the inflammatory diseases listed
hereinafter, but are not limited thereto, such as septic shock,
hemodynamic shock, malaria, inflammatory bowel diseases (IBDs) such
as Crohn's disease and ulcerative colitis, inflammatory bone
diseases, mycobacterial infections, meningitis, fibrotic diseases,
cardiac diseases, atherosclerosis, obesity, ischemic attack,
transplant rejection, cancer, diseases involving angiogenesis
phenomena, autoimmune diseases, osteoarthritis, rheumatoid
arthritis, ankylosing spondylitis, juvenile chronic arthritis,
multiple sclerosis, HIV, non-insulin-dependent diabetes mellitus,
allergic diseases, asthma, chronic obstructive pulmonary disease
(COPD), inflammatory skin diseases, psoriasis, atopic dermatitis
and psoriatic arthritis.
These molecules are also potential active ingredients for the
treatment of neurological pathological conditions with an
inflammatory nature, for which reducing TNF.alpha. production would
be of great interest. These pathological conditions listed
hereinafter in a nonlimiting manner are, for example, Alzheimer's
disease, Parkinson's disease, parkinsonian disorders, amyotrophic
lateral sclerosis, autoimmune diseases of the nervous system,
autonomic diseases of the nervous system, dorsal pain, cerebral
edema, cerebrovascular disorders, dementia, nervous system nerve
fiber demyelinating autoimmune diseases, diabetic neuropathies,
encephalitis, encephalomyelitis, epilepsy, chronic fatigue
syndrome, giant cell arteritis, Guillain-Barre syndrome, headaches,
multiple sclerosis, neuralgia, peripheral nervous system diseases,
polyneuropathies, polyradiculoneuropathy, radiculopathy,
respiratory paralysis, spinal cord diseases, Tourette's syndrome,
central nervous system vasculitis, Huntington's disease and
stroke.
The invention relates to the use of a compound of general formula
(I) as defined above, for preparing a medicament intended for the
treatment of pathological conditions with an inflammatory nature,
in which TNF.alpha. is involved.
The invention relates to the use of a compound of general formula
(I) as defined above, for preparing a medicament intended for the
treatment of inflammatory skin diseases, of psoriasis, of atopic
dermatitis or of psoriatic arthritis.
A subject of the present invention is also a pharmaceutical
composition intended in particular for the treatment of the
abovementioned conditions, and which is characterized in that it
comprises, in a carrier which is pharmaceutically acceptable and
compatible with the method of administration selected for this
composition, at least one compound of general formula (I). This
compound of general formula (I) can also be in one of its
enantiomeric forms or in the form of one of its pharmaceutically
acceptable salts.
Several examples of preparation of active compounds of formula (I)
according to the invention, and also of the results of biological
activity of such compounds, will now be given by way of
illustration and without being in any way limiting in nature.
EXEMPLARY EMBODIMENTS
The compounds of general formula (I) are characterized by proton
NMR analysis on a Bruker Avance 400 MHz instrument.
EXAMPLE 1
3-[(4-but-2-ynyloxybenzenesulfonyl)methylamino]-N-hydroxy-2-(4-methanesulf-
onylpiperazin-1-yl)propionamide
1-1: Dimethyl 2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate
19.5 g (141 mmol) of potassium carbonate and then 19.5 ml (134
mmol) of dimethyl bromomalonate are added to a solution of 25 g
(134 mmol) of tert-butyl piperazine-1-carboxylate in 300 ml of
acetonitrile. The reaction medium is stirred at ambient temperature
for 24 h and then filtered in order to remove the insoluble salts,
and concentrated under vacuum. The crude residue obtained is
purified by chromatography on silica gel, elution being carried out
with a 70/30 heptane/ethyl acetate mixture. 41 g (97%) of dimethyl
2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate are obtained in the
form of a light oil.
1-2: Dimethyl
2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(1,3-dioxo-1,3-dihydroisoindol--
2-ylmethyl)malonate
3.5 g (87 mmol) of sodium hydride are added portionwise to a
solution of 25 g (87 mmol) of dimethyl
2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate in 250 ml of
tetrahydrofuran cooled to 2.degree. C. The reaction medium is
stirred at ambient temperature for 30 minutes and then brought back
to 2.degree. C., before adding, dropwise, 21 g (87 mmol) of
2-bromomethylisoindole-1,3-dione in 200 ml of tetrahydrofuran. The
reaction medium is stirred at ambient temperature for 20 h, treated
by adding 500 ml of water and then extracted with ethyl acetate.
The organic phase is dried over magnesium sulfate, filtered, and
concentrated under vacuum.
The crude product obtained is purified by chromatography on silica
gel, elution being carried out with a 70/30 heptane/ethyl acetate
mixture. 27.5 g (73%) of dimethyl
2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(1,3-dioxo-1,3-dihydroisoindol--
2-ylmethyl)malonate are obtained in the form of a white solid.
1-3: Dimethyl
2-aminomethyl-2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate
A solution of 2.9 ml (64 mmol) of hydrazine hydrate in 8 ml of
methanol is added to a solution of 27.5 g (58 mmol) of dimethyl
2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(1,3-dioxo-1,3-dihydroisoindol--
2-ylmethyl)malonate in 300 ml of methanol cooled beforehand to
-5.degree. C. The reaction medium is stirred at from -5.degree. C.
to ambient temperature over the course of 3 h. After evaporation
and addition of 300 ml of water, the reaction medium is extracted
with ethyl acetate. The organic phases are washed with a saturated
aqueous solution of sodium hydrogen carbonate, dried over magnesium
sulfate, filtered and evaporated. The residue obtained is purified
by chromatography on silica gel, elution being carried out with an
8/2 heptane/ethyl acetate mixture and then an increase in polarity
up to a 90/10 ethyl acetate/methanol mixture. 10 g (50%) of
dimethyl
2-aminomethyl-2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate are
thus obtained in the form of a light oil.
1-4: Dimethyl
2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[(4-but-2-ynyloxybenzenesulfony-
lamino)-methyl]malonate
1.1 ml (8 mmol) of triethylamine and then 1.8 ml (7 mmol) of
4-but-2-ynyloxybenzenesulfonyl chloride are added to a solution of
2.5 g (7 mmol) of dimethyl
2-aminomethyl-2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate in 30
ml of dichloromethane. The reaction medium is stirred at ambient
temperature for 2 hours and then concentrated under vacuum. The
crude product obtained is purified by chromatography on silica gel,
elution being carried out with a 70/30 heptane/ethyl acetate
mixture. 2.1 g (51%) of dimethyl
2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[(4-but-2-ynyloxybenze-
nesulfonylamino)methyl]malonate are obtained in the form of a white
solid.
1-5: Dimethyl
2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]-2-piperazin-1-ylmalonate
2.8 ml of trifluoroacetic acid are added to a solution of 2.1 g (4
mmol) of dimethyl
2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[(4-but-2-ynyloxybenzenesulfony-
lamino)methyl]malonate diluted in 30 ml of dichloromethane. After
stirring at ambient temperature for 24 h, a saturated aqueous
solution of sodium hydrogen carbonate is added to pH=8 and the
reaction medium is extracted with dichloromethane. The organic
phases are combined, washed with water, dried over magnesium
sulfate, and then filtered and evaporated. 1.7 g (98%) of dimethyl
2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]-2-piperazin-1-ylmalonate
are obtained in the form of a white solid.
1-6: Dimethyl
2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]-2-(4-methanesulfonylpiper-
azin-1-yl)malonate
0.6 ml (4 mmol) of triethylamine and then 0.3 ml (4 mmol) of
methanesulfonyl chloride are added to a solution of 1.6 g (4 mmol)
of dimethyl
2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]-2-piperazin-1-yl-
malonate diluted in 30 ml of dichloromethane. The reaction medium
is then stirred at ambient temperature for 3 h and then evaporated
to dryness. The crude residue is purified by chromatography on
silica gel, elution being carried out with a 99/1
dichloromethane/methanol mixture. 1.1 g (58%) of dimethyl
2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]-2-(4-methanesulfonylpiper-
azin-1-yl)malonate are obtained in the form of a white solid.
1-7: Dimethyl
2-{(4-but-2-ynyloxybenzenesulfonyl)methylamino]methyl}-2-(4-methanesulfon-
ylpiperazin-1-yl)malonate
120 mg (0.9 mmol) of potassium carbonate and then 56 .mu.l (0.9
mmol) of methyl iodide are added to a solution of 400 mg (0.8 mmol)
of dimethyl
2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]-2-(4-methanesulfonylpiper-
azin-1-yl)malonate in 10 ml of dimethylformamide. The reaction
medium is then stirred at ambient temperature for 18 h and then
hydrolyzed by adding water and extracted with ethyl acetate. The
organic phases are washed with water and then dried over magnesium
sulfate, filtered and concentrated under vacuum. The crude product
obtained is purified by chromatography on silica gel, elution being
carried out with a 50/50 heptane/ethyl acetate mixture. 410 mg
(100%) of dimethyl
2-{[(4-but-2-ynyloxybenzenesulfonyl)methylamino]methyl}-2-(4-methanesulfo-
nylpiperazin-1-yl)malonate are obtained in the form of a white
solid.
1-8:
3-[(4-But-2-ynyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylp-
iperazin-1-yl)propanoic acid
1.7 ml (1.7 mmol) of an aqueous solution of sodium hydroxide having
a concentration of 1M are added to a solution of 270 mg (0.5 mmol)
of dimethyl
2-{[(4-but-2-ynyloxybenzenesulfonyl)methylamino]-methyl}-2-(4-me-
thanesulfonylpiperazin-1-yl)malonate in 7 ml of tetrahydrofuran and
2 ml of methanol. The reaction medium is stirred at 40.degree. C.
for 15 h and then brought back to pH=6 by adding an aqueous
solution of hydrochloric acid having a concentration of 1M. After
evaporation of the solvents under vacuum, the product precipitates.
The residue obtained is taken up in 5 ml of water and stirred for
30 min until precipitation occurs. The product is filtered off,
rinsed with water and then dried under vacuum. 200 mg (87%) of
3-[(4-but-2-ynyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylpiper-
azin-1-yl)propanoic acid are obtained in the form of a white
solid.
1-9:
3-[(4-But-2-ynyloxybenzenesulfonyl)methylamino]-N-hydroxy-2-(4-methan-
esulfonylpiperazin-1-yl)propionamide
63 mg (0.5 mmol) of 1-hydroxybenzotriazole and then 88 mg (0.5
mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride are added to a solution of 200 mg (0.4 mmol) of
3-[(4-but-2-ynyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylpiper-
azin-1-yl)propanoic acid in 6 ml of dimethylformamide. The reaction
medium is stirred for 10 min at ambient temperature and then 68 mg
(0.5 mmol) of O-tert-butyldimethysilylhydroxylamine are added. The
reaction medium is then stirred at ambient temperature for 24 h,
hydrolyzed by adding 2 ml of a 5% aqueous citric acid solution, and
stirred for a further 30 minutes. After extraction with ethyl
acetate, the organic phase is washed with water, dried over
magnesium sulfate, filtered and concentrated. The crude residue is
purified by chromatography on silica gel, elution being carried out
with a 95/5 dichloromethane/methanol mixture. 100 mg (50%) of
3-[(4-but-2-ynyloxybenzenesulfonyl)methylamino]-N-hydroxy-2-(4-methanesul-
fonylpiperazin-1-yl)propionamide are obtained in the form of a
white solid with a melting point of 86.degree. C.
.sup.1H NMR (.delta., DMSO): 1.91 (s, 3H); 2.63-2.68 (m, 2H); 2.72
(s, 3H); 2.72-2.75 (m, 2H); 2.92 (s, 3H); 3.05-3.15 (m, 5H);
3.30-3.38 (m, 2H); 4.93 (s, 2H); 7.24 (d, J=6.8 Hz, 2H); 7.79 (d,
J=6.8 Hz, 2H); 9.06 (s, 1H); 10.77 (s, 1H).
EXAMPLE 2
(S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-N-hydroxy-2-(4-methanesulfonyl-
piperazin-1-yl)propionamide
2.1: Sodium salt of 4-but-2-ynyloxybenzenesulfonic acid
50 g (370 mmol) of 1-bromo-2-butyne are added to a solution of 43 g
(185 mmol) of commercial sodium salt of 4-hydroxybenzenesulfonic
acid and of 185 ml (185 mmol) of an aqueous solution of sodium
hydroxide having a concentration of 1M, in 800 ml of isopropanol.
The reaction medium is heated at 70.degree. C. for 18 h.
After evaporation of the isopropanol, the product obtained is
filtered, rinsed with isopropanol and with diethyl ether and then
dried under vacuum. 46 g (100%) of the sodium salt of
4-but-2-ynyloxybenzenesulfonic acid are obtained in the form of a
white solid.
2.2: 4-But-2-ynyloxybenzenesulfonyl chloride
30 g (107 mmol) of the sodium salt of
4-but-2-ynyloxybenzenesulfonic acid in 120 ml of dimethylformamide
are added dropwise to a solution of 28 ml (321 mmol) of oxalyl
chloride in 120 ml of dichloromethane, cooled beforehand to
-10.degree. C., and then the reaction medium is stirred at ambient
temperature for 18 h. 800 ml of ice are added and the medium is
extracted with ethyl acetate. The organic phases are combined,
washed with water, dried over magnesium sulfate, filtered and
concentrated under vacuum. 22 g (84%) of
4-but-2-ynyloxybenzenesulfonyl chloride are obtained in the form of
a beige solid.
2.3: N,N-bis(2-Chloroethyl)methanesulfonamide
8.6 ml (62 mmol) of triethylamine are added to a solution of 5 g
(28 mmol) of bis(2-chloroethyl)amine hydrochloride in 60 ml of
dichloromethane. The triethylammonium chloride salts precipitate
and are filtered off. 2.4 ml (31 mmol) of methylsulfonyl chloride
are then added to the filtrate obtained, and the reaction medium is
stirred at ambient temperature for 3 h. After the addition of
water, the product is extracted with dichloromethane. The organic
phase is washed with water, dried over magnesium sulfate, filtered
and concentrated. 5.8 g (94%) of
N,N-bis(2-chloroethyl)methanesulfonamide are obtained in the form
of a beige solid.
2.4: Methyl
(S)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propano-
ate
In a Schlenk tube, a solution of 5 g (20 mmol) of methyl
(S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride and
4.3 g (20 mmol) of N,N-bis(2-chloroethyl)methanesulfonamide in 65
ml of N,N-diisopropylethylamine is heated at 127.degree. C. with
vigorous stirring for 18 h. After the addition of water, the
product is extracted with ethyl acetate. The organic phases are
combined, washed with water, dried over magnesium sulfate, filtered
and concentrated under vacuum. The crude product obtained is
purified by chromatography on silica gel, elution being carried out
with a 50/50 heptane/ethyl acetate mixture. 3.3 g (46%) of methyl
(S)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propano-
ate are obtained in the form of a white solid.
2.5: Methyl
(S)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoate
hydrochloride
15 ml of a solution of hydrochloric acid in isopropanol, having a
concentration of 5-6N are added dropwise to a solution of 2.7 g
(7.4 mmol) of methyl
(S)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propano-
ate in 30 ml of methanol. The reaction medium is stirred at
40.degree. C. for 2 h, concentrated under vacuum, and then taken up
in 20 ml of methanol and 150 ml of diethyl ether. The product
precipitates, and is filtered off under vacuum, rinsed with diethyl
ether and then dried under vacuum. 2.3 g (100%) of methyl
(S)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoate
hydrochloride are obtained in the form of a white solid.
2.6: Methyl
(S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-
-1-yl)propanoate
0.3 ml (2 mmol) of triethylamine and 270 mg (1 mmol) of
4-but-2-ynyloxybenzenesulfonyl chloride (prepared as described in
2.2) are added to a solution of 300 mg (1 mmol) of methyl
(S)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoate
hydrochloride (prepared as described in 2.5) in 8 ml of
dichloromethane. After stirring at ambient temperature for 18 h,
water is added and the reaction medium is extracted with
dichloromethane. The organic phases are washed with water, dried
over magnesium sulfate, filtered and concentrated.
The crude product obtained is purified by chromatography on silica
gel, elution being carried out with a 50/50 heptane/ethyl acetate
mixture. 400 mg (85%) of methyl
(S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-
-1-yl)propanoate are obtained in the form of a white solid.
2.7:
(S)-3-(4-But-2-ynyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiper-
azin-1-yl)propanoic acid
1.3 ml (1.3 mmol) of an aqueous solution of lithium hydroxide
having a concentration of 1M are added to a solution of 400 mg (0.8
mmol) of methyl
(S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-2-(4-methanesulfonylpi-
perazin-1-yl)propanoate diluted in 10 ml of tetrahydrofuran cooled
beforehand to 0.degree. C. The reaction medium is stirred at
ambient temperature for 20 h. After evaporation to dryness, 1.5 ml
of an aqueous solution of acetic acid having a concentration of 1M
are added so as to obtain a pH=6. The product precipitates, and is
filtered off, rinsed with water and then with diethyl ether and
dried under vacuum. 340 mg (89%) of
(S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-
-1-yl)propanoic acid are obtained in the form of a white solid.
2.8:
(S)-3-(4-But-2-ynyloxybenzenesulfonylamino)-N-hydroxy-2-(4-methanesul-
fonylpiperazin-1-yl)propionamide
120 mg (0.9 mmol) of 1-hydroxybenzotriazole and 170 mg (0.9 mmol)
of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride are
added to a solution of 340 mg (0.7 mmol) of
(S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-
-1-yl)propanoic acid in 8 ml of dimethylformamide. The reaction
medium is stirred for 30 min, and then 120 mg (0.8 mmol) of
O-tert-butyldimethysilylhydroxylamine in 3 ml of dimethylformamide
are added. The reaction medium is then stirred at ambient
temperature for 20 h, and then hydrolyzed with 2 ml of water and 2
ml of a 5% aqueous solution of citric acid. After stirring for 30
min, a saturated aqueous solution of sodium hydrogen carbonate is
added to pH=8, and then the reaction medium is extracted with ethyl
acetate. The organic phase is dried over magnesium sulfate,
filtered and concentrated. The residue is taken up in
dichloromethane, filtered, and then dried under vacuum. 80 mg (23%)
of
(S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-N-hydroxy-2-(4-metha-
nesulfonylpiperazin-1-yl)propionamide are obtained in the form of a
white solid with a melting point of 150.degree. C.
.sup.1H NMR (.delta., DMSO): 1.86 (s, 3H); 2.55 (m, 4H); 2.83 (s,
3H); 2.85-2.88 (m, 1H); 2.97-3.00 (m, 3H); 3.00-3.06 (m, 2H);
3.10-3.12 (t, J=4.8 Hz, 1H); 4.86 (s, 2H); 7.15 (d, J=9.2 Hz, 2H);
7.51 (s, 1H); 7.75 (d, J=9.2 Hz, 2H); 8.94 (s, 1H); 10.6 (s,
1H).
EXAMPLE 3
(S)-3-(4-benzyloxy-benzenesulfonylamino)-N-hydroxy-2-(4-methanesulfonyl-pi-
perazin-1-yl)propionamide
3.1: N,N-bis-(2-Chloroethyl)methanesulfonamide
14.3 ml (185 mmol) of methanesulfonyl chloride are added slowly to
a solution of 15 g (84 mmol) of commercial bis(2-chloroethylamine)
hydrochloride and 26 ml (185 mmol) of triethylamine in 200 ml of
dichloromethane and 70 ml of tetrahydrofuran previously stirred for
15 min and then filtered in order to remove the triethylammonium
chloride. The reaction medium is then stirred at ambient
temperature for 18 h, extracted with dichloromethane, and washed
with water. The organic phase is dried over magnesium sulfate,
filtered and evaporated. The residue obtained is washed with
diisopropyl ether, filtered and then dried under vacuum. 15.3 g
(82%) of N,N-bis-(2-chloroethyl)methanesulfonamide are obtained in
the form of a solid.
3.2: Methyl
(S)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propano-
ate
A solution of 9.6 g (44 mmol) of
N,N-bis-(2-chloroethyl)methanesulfonamide and 11.1 g (44 mmol) of
methyl 2-amino-3-tert-butoxypropanoate hydrochloride in 90 ml of
diisopropylethylamine is heated at 127.degree. C. for 18 h. The
reaction medium is evaporated to dryness. 31 g of crude residue are
obtained and purified by chromatography on silica gel, elution
being carried out with a 9/1 heptane/ethyl acetate mixture and then
an increase in polarity up to 4/6. 5.5 g (35%) of methyl
(S)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propano-
ate are obtained.
3.3: Methyl
(S)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoate
dihydrochloride
A solution of 4 g (11 mmol) of methyl
(S)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propano-
ate (prepared as described in example 2.4) in 40 ml of methanol and
20 ml of a solution of hydrochloric acid in isopropanol, having a
concentration of 5 or 6M, is stirred at 40.degree. C. for 18 h and
then concentrated under vacuum. The residue obtained is taken up in
200 ml of diethyl ether, filtered, and then dried under vacuum, 3.5
g (94%) of methyl
(S)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoate
dihydrochloride are obtained in the form of a beige solid.
3.4: Sodium salt of 4-benzyloxybenzenesulfonic acid
64 ml (539 mmol) of benzyl bromide are added to a solution of 50 g
(215 mmol) of the sodium salt of 4-hydroxybenzenesulfonic acid
dihydrate in 700 ml of isopropanol and 250 ml (250 mmol) of an
aqueous solution of sodium hydroxide having a concentration of 1M.
The reaction medium is heated at 70.degree. C. for 20 h. After
concentration of the isopropanol under vacuum, the product
precipitates and is filtered off. 61 g (100%) of the sodium salt of
4-benzyloxybenzenesulfonic acid are obtained in the form of a white
solid.
3.5: 4-Benzyloxybenzenesulfonyl chloride
A solution of 55 ml (639 mmol) of oxalyl chloride in 250 ml of
dichloromethane is added dropwise to a solution of 61 g (213 mmol)
of the sodium salt of 4-benzyloxybenzenesulfonic acid in 200 ml of
dimethylformamide, while maintaining the temperature between
-20.degree. C. and -10.degree. C. After addition, the reaction
medium is slowly brought back to ambient temperature and then
stirred for 18 h, poured onto ice and extracted with ethyl acetate.
The organic phase is washed with water and with a saturated aqueous
solution of sodium chloride and concentrated under vacuum. 54 g
(89%) of 4-benzyloxybenzenesulfonyl chloride are obtained in the
form of a white solid.
3.6: Methyl
(S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-y-
l)propanoate
1.1 ml (7.8 mmol) of triethylamine and then 730 mg (2.6 mmol) of
4-benzyloxybenzenesulfonyl chloride in 8 ml of dichloromethane are
added to a solution of 800 mg (2.4 mmol) of methyl
(S)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoate
dihydrochloride in 20 ml of dichloromethane and the reaction medium
is stirred at ambient temperature for 3 h. After the addition of
water, the product is extracted with dichloromethane. The organic
phase is washed with water, dried over magnesium sulfate, filtered
and concentrated.
The residue obtained is purified by chromatography on silica gel,
elution being carried out with an 8/2 heptane/ethyl acetate
mixture. 0.9 g (75%) of methyl
(S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpip-
erazin-1-yl)propanoate are obtained in the form of a white
solid.
3.7:
(S)-3-(4-Benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-
-1-yl)propanoic acid
2.6 ml (2.6 mmol) of an aqueous solution of lithium hydroxide
having a concentration of 1M are added to a solution of 900 mg (1.8
mmol) of methyl
(S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpipera-
zin-1-yl)propanoate in 20 ml of tetrahydrofuran and 0.5 ml of
water. The reaction medium is stirred at ambient temperature for 18
h and then the THF is evaporated off under vacuum. 2.8 ml of an
aqueous solution of acetic acid having of concentration of 1M and
then 30 ml of water are added and the product precipitates. The
suspension is stirred for 30 min at 100.degree. C. and then brought
back to ambient temperature, filtered and dried under vacuum. 750
mg (86%) of
(S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-y-
l)propanoic acid are obtained in the form of a white solid.
3.8:
(S)-3-(4-Benzyloxybenzenesulfonylamino)-N-hydroxy-2-(4-methanesulfony-
l-piperazin-1-yl)propionamide
224 mg (1.7 mmol) of 1-hydroxybenzotriazole and 318 mg (1.7 mmol)
of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride are
added successively to 750 mg (1.5 mmol) of
(S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-y-
l)propanoic acid in 20 ml of dimethylformamide. After stirring at
ambient temperature for 20 min, a solution of 244 mg (1.7 mmol) of
O-tert-butyldimethylsilylhydroxylamine in 3 ml of dimethylformamide
is added. The reaction medium is then stirred at ambient
temperature for 18 h and then 2 ml of a saturated aqueous solution
of sodium hydrogen carbonate and finally 2 ml of water are added.
After extraction with ethyl acetate, the organic phase is washed
with a saturated aqueous solution of sodium hydrogen carbonate,
dried over magnesium sulfate, filtered and concentrated. The crude
residue obtained is taken up in 15 ml of ethyl acetate, heated to
70.degree. C. and then brought back to ambient temperature,
filtered and dried under vacuum.
300 mg (34%) of
(S)-3-(4-benzyloxybenzenesulfonylamino)-N-hydroxy-2-(4-methanesulfonylplp-
erazin-1-yl)propionamide are obtained in the form of a white solid
having a melting point of 165.degree. C.
.sup.1H NMR (.delta., DMSO): 2.40-2.50 (m, 2H); 2.50-2.60 (m, 2H);
2.84 (s, 3H), 3.00-3.05 (m, 4H); 3.06-3.09 (m, 2H); 3.34 (s, 1H);
5.19 (s, 2H); 7.19 (d, J=8.4 Hz, 2H); 7.30-7.34 (m, 1H); 7.35-7.47
(m, 5H); 7.73 (d, J=8.4 Hz, 2H); 8.93 (s, 1H); 10.65 (s, 1H).
EXAMPLE 4
(S)-3-[(4-Benzyloxybenzenesulfonyl)methylamino]-N-hydroxy-2-(4-methanesulf-
onylpiperazin-1-yl)propionamide
4.1: Methyl
(S)-3-[(4-benzyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylpiper-
azin-1-yl)propanoate
300 mg (1.9 mmol) of potassium carbonate and then 0.2 ml (3.1 mmol)
of methyl iodide are added to a solution of 800 mg (1.6 mmol) of
methyl
(S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-y-
l)propanoate (prepared as described in 3.6) in 15 ml of
dimethylformamide. The reaction medium is then stirred at ambient
temperature for 20 h, hydrolyzed, and then diluted with ethyl
acetate. The product is extracted with ethyl acetate. The organic
phases are washed with water, dried over magnesium sulfate and
filtered.
The filtrate is concentrated under vacuum, to give 820 mg (100%) of
methyl
(S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpipera-
zin-1-yl)propanoate in the form of a white solid.
4.2:
(S)-3-[(4-Benzyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylp-
iperazin-1-yl)propanoic acid
In a manner analogous to example 3.7, using 820 mg (1.6 mmol) of
methyl
(S)-3-[(4-benzyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylpiper-
azin-1-yl)propanoate, 720 mg (90%) of
(S)-3-[(4-benzyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylpiper-
azin-1-yl)propanoic acid are obtained in the form of a white
solid.
4.3:
(S)-3-[(4-Benzyloxybenzenesulfonyl)methylamino]-N-hydroxy-2-(4-methan-
esulfonylpiperazin-1-yl)propionamide
In a manner analogous to example 3.8, using 720 mg (1.4 mmol) of
(S)-3-[(4-benzyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylpiper-
azin-1-yl)propanoic acid, 360 mg (49%) of
(S)-3-[(4-benzyloxybenzenesulfonyl)methylamino]-N-hydroxy-2-(4-methanesul-
fonylpiperazin-1-yl)propionamide are obtained in the form of a
white solid with a melting point of 110.degree. C.
.sup.1H NMR (.delta., DMSO): 2.58-2.63 (m, 2H); 2.65 (s, 3H);
2.67-2.73 (m, 2H); 2.86 (s, 3H); 2.98-3.05 (m, 4H); 3.05-3.09 (m,
1H); 3.24-3.25 (m, 1H); 3.28-3.31 (m, 1H); 5.21 (s, 2H); 7.24 (d,
J=8.9 Hz, 2H); 7.34-7.44 (m, 3H); 7.48 (d, J=7.2 Hz, 2H); 7.72 (d,
J=8.9 Hz, 2H); 8.99 (s, 1H); 10.69 (s, 1H).
EXAMPLE 5
(S)--N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin--
4-ylmethoxy)benzenesulfonylamino]propionamide
5.1: Methyl
(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)-
propanoate
A solution of 2.0 g (3.9 mmol) of methyl
(S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-y-
l)propanoate (prepared as described in example 3.6) in 60 ml of
ethanol, 30 ml of dioxane and 0.5 ml of glacial acetic acid is
degassed under a nitrogen stream and then 200 mg (10% by weight) of
palladium-on-carbon at 10% in suspension in 3 ml of dioxane are
added. The reaction medium is placed under a hydrogen atmosphere
and stirred at ambient temperature for 18 h. After filtration
through celite, the filtrate is hydrolyzed and then the product is
extracted with ethyl acetate. The organic phase is washed with
water and then with a saturated aqueous solution of sodium
chloride, dried over magnesium sulfate, filtered and concentrated
under vacuum. 1.65 g (100%) of methyl
(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)-
propanoate are obtained in the form of a white solid.
5.2: Methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethox-
y)benzenesulfonylamino]propanoate
280 mg (0.85 mmol) of cesium carbonate followed by 160 mg (0.85
mmol) of 4-chloromethyl-2-methylquinoline and by 15 mg of potassium
iodide are added to a solution of 300 mg (0.71 mmol) of methyl
(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)-
propanoate in 10 ml of acetone. The reaction medium is stirred at
ambient temperature for 18 h, filtered and concentrated under
vacuum. The crude product is purified by chromatography on silica
gel, elution being carried out with a 40/60 heptane/ethyl acetate
mixture. 130 mg (32%) of methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-y-
lmethoxy)benzenesulfonylamino]propanoate are obtained in the form
of a white solid.
5.3:
(S)-2-(4-Methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylme-
thoxy)benzenesulfonylamino]propanoic acid
In a manner analogous to example 3.7, using 130 mg (0.2 mmol) of
methyl
(S)-2-(4-methanesulfonyl-piperidin-1-yl)-3-[4-(2-methylquinolin-4-ylmetho-
xy)benzenesulfonylamino]propanoate, 120 mg (99%) of
(S)-2-(4-methanesulfonylpiperidin-1-yl)-3-[4-(2-methylquinolin-4-ylmethox-
y)benzenesulfonylamino]-propanoic acid are obtained in the form of
a white solid.
5.4:
(S)--N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquin-
olin-4-ylmethoxy)benzenesulfonylamino]propionamide
In a manner analogous to example 3.8, using 123 mg (0.2 mmol) of
(S)-2-(4-methanesulfonyl-piperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmetho-
xy)benzenesulfonylamino]propanoic acid, 90 mg (69%) of
(S)--N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-
-4-ylmethoxy)-benzenesulfonylamino]propionamide are obtained in the
form of a solid with a melting point of 185.degree. C.
.sup.1H NMR (.delta., DMSO): 2.54-2.60 (m, 4H); 2.72 (s, 3H); 2.88
(s, 3H), 2.88-2.93 (m, 1H); 3.01-3.05 (m, 1H); 3.06-3.12 (m, 4H);
3.13-3.16 (t, J=7 Hz, 1H); 5.76 (s, 2H); 7.38 (d, J=8 Hz, 2H); 7.57
(s, 1H); 7.61-7.66 (m, 2H); 7.78-7.85 (m, 3H); 8.02 (d, J=8.2 Hz,
1H); 8.15 (d, J=8.2 Hz, 1H); 8.98 (s, 1H); 10.71 (s, 1H).
EXAMPLE 6
(S)--N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(naphthalen-1-ylme-
thoxy)benzenesulfonylamino]propionamide
6.1: Methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethox-
y)benzenesulfonylamino]propanoate
In a manner analogous to example 5.2, using 160 mg (0.9 mmol) of
4-chloromethyl-2-methylquinoline and 300 mg (0.7 mmol) of methyl
(S)-3-(4-hydroxy-benzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl-
)propanoate (prepared as described in 5.1), 130 mg (32%) of methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethox-
y)benzenesulfonylamino]-propanoate are obtained in the form of a
white solid.
6.2:
(S)-2-(4-Methanesulfonylpiperazin-1-yl)-3-[4-(naphthalen-1-ylmethoxy)-
benzenesulfonylamino]-propanoic acid
In a manner analogous to example 3.7, using 240 mg (0.6 mmol) of
methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(naphthalen-1-ylmethoxy)benz-
enesulfonylamino]propanoate, 210 mg (91%) of
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(naphthalen-1-ylmethoxy)benz-
ene-sulfonylamino]-propanoic acid are obtained in the form of a
white solid.
6.3:
(S)--N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(naphthalen-1-
-ylmethoxy)benzenesulfonylamino]propionamide
In a manner analogous to example 3.8, using 210 mg (0.4 mmol) of
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(naphthalen-1-ylmethoxy)benz-
enesulfonylamino]propanoic acid, 70 mg (33%) of
(S)--N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(naphthalen-1-ylm-
ethoxy)-benzenesulfonylamino]propionamide are obtained in the form
of a beige solid with a melting point of 148.degree. C.
.sup.1H NMR (.delta., DMSO): 2.45 (m, 2H); 2.60 (m, 2H); 2.85 (s,
3H); 2.90-3.05 (m, 4H); 3.06-3.15 (m, 2H); 3.35 (s, 1H); 5.66 (s,
2H); 7.30 (d, J=8.4 Hz, 2H); 7.50-7.60 (m, 4H); 7.70 (d, J=6.2 Hz,
1H); 7.77 (d, J=8.2 Hz, 2H); 7.95-8.05 (m, 2H); 8.10 (d, J=6.4 Hz,
1H); 8.94 (s, 1H); 10.70 (s, 1H).
EXAMPLE 7
(S)--N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzene-sul-
fonylamino)propionamide
7.1: Methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzenesulfonylamino)-
propanoate
In a manner analogous to example 5.2, using 0.1 ml (1.3 mmol) of
1-bromopropane and 400 mg (0.95 mmol) of methyl
(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)-
propanoate (prepared as described in 5.1), 220 mg (50%) of methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzenesulfonylamino)-
propanoate are obtained in the form of a colorless oil.
7.2:
(S)-2-(4-Methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzenesulfonylam-
ino)propanoic acid
In a manner analogous to example 3.7, using 220 mg (0.5 mmol) of
methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzenesulfonylamino)-
propanoate, 190 mg (90%) of
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzenesulfonylamino)-
propanoic acid are obtained in the form of a white solid.
7.3:
(S)--N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzen-
esulfonylamino)-propionamide
In a manner analogous to example 3.8, using 190 mg (0.4 mmol) of
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzenesulfonylamino)-
propanoic acid, 30 mg (16%) of
(S)--N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzenesul-
fonylamino)propionamide are obtained in the form of a white solid
with a melting point of 137.degree. C.
.sup.1H NMR (.delta., DMSO): 0.91 (t, J=7.3 Hz, 3H); 1.63-1.73 (m,
2H); 2.45 (m, 2H); 2.55 (m, 2H); 2.77 (s, 3H); 2.82 (m, 1H);
2.83-2.95 (m, 4H); 2.95-3.05 (m, 2H); 3.94 (t, J=6.4 Hz, 2H); 7.03
(d, J=8.7 Hz, 2H); 7.38 (m, 1H); 7.65 (d, J=8.7 Hz, 2H); 8.85 (s,
1H); 10.58 (s, 1H).
EXAMPLE 8
(S)-3-[4-(3-Cyanobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-(4-methanesul-
fonylpiperazin-1-yl)propionamide
8.1: Methyl
(S)-3-[4-(3-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpipe-
razin-1-yl)propanoate
In a manner analogous to example 5.2, using 205 mg (1 mmol) of
3-(bromomethyl)benzonitrile and 400 mg (0.95 mmol) of methyl
(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)-
propanoate (prepared as described in example 5.1), 295 mg (58%) of
methyl
(S)-3-[4-(3-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpipe-
razin-1-yl)propanoate are obtained in the form of a white
solid.
8.2:
(S)-3-[4-(3-Cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonyl-
piperazin-1-yl)propanoic acid
In a manner analogous to example 3.7, using 295 mg (0.5 mmol) of
methyl
(S)-3-[4-(3-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpipe-
razin-1-yl)propanoate, 270 mg (94%) of
(S)-3-[4-(3-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpipe-
razin-1-yl)propanoic acid are obtained in the form of a white
solid.
8.3:
(S)-3-[4-(4-Cyanobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-(4-metha-
nesulfonylpiperazin-1-yl)propionamide
In a manner analogous to example 3.8, using 264 mg (0.5 mmol) of
(S)-3-[4-(3-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpipe-
razin-1-yl)propanoic acid, 107 mg (40%) of
(S)-3-[4-(3-cyanobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-(4-methanesu-
lfonyl-piperazin-1-yl)propionamide are obtained in the form of a
beige powder with a melting point of 108.degree. C.
.sup.1H NMR (.delta., DMSO): 2.55 (m, 4H); 2.84 (s, 3H); 2.95-3.05
(m, 4H); 3.10 (t, J=6.4 Hz, 1H); 3.34 (m; 2H); 5.26 (s, 2H); 7.22
(d, J=8.6 Hz, 2H); 7.50 (s, 1H); 7.64 (t, J=7.6 Hz, 1H); 7.76 (d,
J=8.6 Hz, 2H); 7.83 (t, J=8 Hz, 2H); 7.96 (s, 1H); 8.93 (s, 1H);
10.66 (s, 1H).
EXAMPLE 9
(S)-3-[4-(4-Cyanobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-(4-methanesul-
fonylpiperazin-1-yl)propionamide
9.1: Methyl
(S)-3-[4-(4-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpipe-
razin-1-yl)propanoate
In a manner analogous to example 5.2, using 400 mg (1 mmol) of
methyl
(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)-
propanoate (prepared as described in 5.1) and 205 mg (1.1 mmol) of
4-(bromomethyl)benzonitrile, 229 mg (45%) of methyl
(S)-3-[4-(4-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpipe-
razin-1-yl)propanoate are obtained in the form of a white
solid.
9.2:
(S)-3-[4-(4-Cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonyl-
piperazin-1-yl)propanoic acid
In a manner analogous to example 3.7, using 229 mg (0.4 mmol) of
methyl
(S)-3-[4-(4-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpipe-
razin-1-yl)propanoate, 202 mg (91%)
(S)-3-[4-(4-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpipe-
razin-1-yl)propanoic acid are obtained in the form of a white
solid.
9.3:
(S)-3-[4-(4-Cyanobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-(4-metha-
nesulfonylpiperazin-1-yl)propionamide
In a manner analogous to example 3.8, using 197 mg (0.4 mmol) of
(S)-3-[4-(4-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpipe-
razin-1-yl)-propanoic acid, 81 mg (40%) of
(S)-3-[4-(4-cyanobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-(4-methanesu-
lfonyl-piperazin-1-yl)propionamide are obtained in the form of a
beige powder with a melting point of 109.degree. C.
.sup.1H NMR (.delta., DMSO): 2.50-2.60 (m, 4H); 2.84 (s, 3H);
2.96-3.01 (m, 4H); 3.09 (t, J=7 Hz, 1H); 3.34 (s, 2H); 5.32 (s,
2H); 7.22 (d, J=8.8 Hz, 2H); 7.50 (m, 1H); 7.66 (d, J=8.1 Hz, 2H);
7.75 (d, J=8.8 Hz, 2H); 7.89 (d, J=8.1 Hz, 2H); 8.93 (s, 1H); 10.66
(s, 1H).
EXAMPLE 10
Benzyl
4-{(S)-1-hydroxycarbamoyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzen-
esulfonylamino]ethyl}piperazine-1-carboxylate
10.1: Benzyl bis(2-chloroethyl)carbamate
13.2 ml (92 mmol) of benzyl chloroformate are added slowly to a
solution, cooled to 0.degree. C., of 15 g (84 mmol) of
bis(2-chloroethylamine) hydrochloride, 26 ml (185 mmol) of
triethylamine in 200 ml of dichloromethane and 70 ml of
tetrahydrofuran, stirred beforehand for 15 min and then filtered in
order to remove the triethylammonium chloride. The reaction medium
is stirred at ambient temperature for 18 h. After the addition of
water, the reaction medium is extracted with ethyl acetate. The
organic phase is dried over magnesium sulfate, filtered and
evaporated. 20 g of crude residue are obtained and purified by
chromatography on silica gel, elution being carried out with an 8/2
heptane/ethyl acetate mixture. 6 g (26%) of benzyl
bis(2-chloroethyl)carbamate are thus obtained.
10.2: Benzyl
4-((S)-2-tert-butoxycarbonylamino-1-methoxycarbonylethyl)piperazine-1-car-
boxylate
A solution of 5.5 g (20 mmol) of benzyl bis(2-chloroethyl)carbamate
and 5.1 g (20 mmol) of methyl 2-amino-3-tert-butoxypropanoate
hydrochloride in 40 ml of diisopropylethylamine is heated at
127.degree. C. for 18 h. After cooling, the reaction medium is
evaporated to dryness. 17 g of crude residue are obtained and
purified by chromatography on silica gel, elution being carried out
with a 9/1 up to 4/6 heptane/ethyl acetate mixture. 1.6 g (19%) of
benzyl
4-((S)-2-tert-butoxycarbonylamino-1-methoxycarbonylethyl)piperazine-1-car-
boxylate.
10.3: Benzyl
4-(2-amino-1-methoxycarbonylethyl)piperazine-1-carboxylate
dihydrochloride
A solution of 1.45 g (3.4 mmol) of benzyl
4-((S)-2-tert-butoxycarbonylamino-1-methoxycarbonylethyl)piperazine-1-car-
boxylate in 3.5 ml of a solution of hydrochloric acid in
isopropanol, having a concentration 5-6N, and 10 ml of methanol is
heated at 40.degree. C. for 3 h and then evaporated. The residue is
taken up in diethyl ether and filtered. 1.2 g (90%) of benzyl
4-(2-amino-1-methoxycarbonylethyl)piperazine-1-carboxylate
dihydrochloride are obtained in the form of a solid.
10.4: Benzyl
4-[(S)-2-(4-hydroxybenzenesulfonylamino)-1-methoxycarbonylethyl]piperazin-
e-1-carboxylate
2.1 ml (15 mmol) of triethylamine and then 920 mg (5 mmol) of
4-hydroxybenzenesulfonyl chloride in 20 ml of dichloromethane are
added dropwise to a solution of 1.1 g (3 mmol) of benzyl
4-(2-amino-1-methoxycarbonylethyl)piperazine-1-carboxylate
dihydrochloride in 30 ml of dichloromethane, cooled beforehand to
0.degree. C. The reaction medium is then stirred at ambient
temperature for 18 h. After the addition of water, the reaction
medium is extracted with dichloromethane. The organic phase is with
water and then dried over magnesium sulfate, filtered and
concentrated under vacuum. The crude residue obtained is purified
by chromatography on silica gel, elution being carried out with a
50/50 heptane/ethyl acetate mixture. 60 mg (46%) of benzyl
4-[2-(4-hydroxybenzenesulfonylamino)-1-methoxycarbonylethyl]pip-
erazine-1-carboxylate are obtained in the form of a white
solid.
10.5: Benzyl
4-{(S)-1-methoxycarbonyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfon-
ylamino]-ethyl}piperazine-1-carboxylate
In a manner analogous to example 5.2, using 260 mg (1.4 mmol) of
4-chloromethyl-2-methylquinoline and 600 mg (1.3 mmol) of benzyl
4-[(S)-2-(4-hydroxybenzenesulfonylamino)-1-methoxycarbonylethyl]-piperazi-
ne-1-carboxylate, 320 mg (40%) of benzyl
4-{(S)-1-methoxycarbonyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfon-
ylamino]ethyl}piperazine-1-carboxylate are obtained in the form of
a white solid.
10.6: Benzyl
4-{(S)-1-carboxy-2-[4-(2-methylquinolin-4-ylmethoxybenzenesulfonylamino]e-
thyl}-piperazine-1-carboxylate
In a manner analogous to example 3.7, using 160 mg (0.25 mmol) of
benzyl
4-{(S)-1-methoxycarbonyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfon-
ylamino]ethyl}piperazine-1-carboxylate, 135 mg (87%) of benzyl
4-{(S)-1-carboxy-2-[4-(2-methylquinolin-4-ylmethoxy-benzenesulfonylamino]-
ethyl}piperazine-1-carboxylate are obtained in the form of a beige
solid.
10.7: Benzyl
4-{(S)-1-hydroxycarbamoyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfo-
nylamino]-ethyl}piperazine-1-carboxylate
In a manner analogous to example 3.8, using 135 mg (0.2 mmol) of
benzyl
4-{(S)-1-carboxy-2-[4-(2-methylquinolin-4-ylmethoxybenzenesulfonylamino]e-
thyl}piperazine-1-carboxylate, 115 mg (82%) of benzyl
4-{(S)-1-hydroxycarbamoyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfo-
nylamino]ethyl}-piperazine-1-carboxylate are obtained in the form
of a white solid with a melting point of 162.degree. C.
.sup.1H NMR (.delta., DMSO): 2.35-2.45 (m, 4H); 2.70 (s, 3H);
2.80-2.90 (m, 1H); 2.95-3.05 (m, 1H); 3.05-3.10 (m, 1H); 3.25-3.40
(m, 4H); 5.05 (s, 2H); 5.74 (s, 2H); 7.29-7.40 (m, 7H); 7.55 (m,
1H); 7.60-7.70 (m, 2H); 7.79 (d, J=8.8 Hz, 3H); 8.01 (d, J=8 Hz,
1H); 8.14 (d, J=8 Hz, 1H); 8.91 (s, 1H); 10.67 (s, 1H).
EXAMPLE 11
(S)--N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin-4-
-ylmethoxy)benzenesulfonylamino]propionamide
11.1: Methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin-4-ylmethoxy-
)benzene-sulfonylamino]propanoate
0.23 ml (1.4 mmol) of diethyl azodicarboxylate is added slowly to a
solution of 400 mg (0.9 mmol) of methyl
(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)-
propanoate (prepared as described in example 5.1), 193 mg (1.0
mmol) of (2-phenylpyridin-4-yl)methanol and 373 mg (1.4 mmol) of
triphenylphosphine in 4 ml of tetrahydrofuran. The reaction mixture
is stirred for one hour at ambient temperature and then evaporated
to dryness. The residue obtained is purified by chromatography on
silica gel, elution being carried out with a 60/40 heptane/ethyl
acetate mixture. 318 mg (57%) of methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin-4-ylmethoxy-
)-benzenesulfonylamino]propanoate are obtained in the form of a
white powder.
11.2:
(S)-2-(4-Methanesulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin-4-ylme-
thoxy)benzenesulfonyl-amino]propanoic acid
In a manner analogous to example 3.7, using 317 mg (0.5 mmol) of
methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin-4-ylmethoxy-
)benzenesulfonylamino]propanoate, 298 mg (96%) of
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin-4-ylmethoxy-
)benzene-sulfonylamino]propanoic acid are obtained in the form of a
white solid.
11.3:
(S)--N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-phenylpyr-
idin-4-ylmethoxy)-benzenesulfonylamino]propionamide
In a manner analogous to example 3.8, using 293 mg (0.5 mmol) of
(S)-2-(4-methane-sulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin-4-ylmethox-
y)benzenesulfonylamino]propanoic acid, 64 mg (21%) of
(S)--N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin--
4-ylmethoxy)benzenesulfonylamino]propionamide are obtained in the
form of a white powder with a melting point of 100.degree. C.
.sup.1H NMR (.delta., DMSO): 2.52-2.59 (m, 4H); 2.84 (s, 3H);
2.85-2.90 (m, 1H); 2.90-3.00 (m, 1H); 3.00-3.08 (m, 4H); 3.10 (t,
J=7.0 Hz, 1H); 5.35 (s, 2H); 7.26 (d, J=8.9 Hz, 2H); 7.42 (m, 1H);
7.45-7.55 (m, 4H); 7.78 (d, J=8.8 Hz, 2H); 8.03 (s, 1H); 8.10 (d,
J=7.0 Hz, 2H); 8.69 (d, J=5.0 Hz, 1H); 8.93 (s, 1H); 10.66 (s,
1H).
EXAMPLE 12
(R)--N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin--
4-ylmethoxy)benzenesulfonylamino]propionamide
12.1: Methyl
(R)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propano-
ate
In a manner analogous to example 3.2, using 3.8 g (17 mmol) of
N,N-bis(2-chloroethyl)-methanesulfonamide (prepared as described in
3.1) and 4 g (16 mmol) of commercial methyl
(R)-2-amino-3-tert-butoxypropanoate hydrochloride, 2.6 g (46%) of
methyl
(R)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propano-
ate are obtained in the form of a light yellow solid.
12.2: Methyl
(R)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoate
dihydrochloride
In a manner analogous to example 3.3, using 2.5 g (7 mmol) of
methyl
(R)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propano-
ate, 2.3 g (100%) of methyl
(R)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoate are
obtained.
12.3: Methyl
(R)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-y-
l)propanoate
In a manner analogous to example 3.6, using 2.4 g (8.4 mmol) of
4-benzyloxybenzenesulfonyl chloride (prepared as described in
example 3.5) and 2.3 g (7.6 mmol) of methyl
(R)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoate
dihydrochloride, 3 g (77%) of methyl
(R)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-y-
l)propanoate are obtained in the form of a solid.
12.4: Methyl
(R)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)-
propanoate
In a manner analogous to example 5.1, using 3 g (5.9 mmol) of
methyl
(R)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-y-
l)propanoate, 2 g (80%) of methyl
(R)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)-
propanoate are obtained in the form of a white solid.
12.5: Methyl
(R)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethox-
y)benzene-sulfonylamino]propanoate
In a manner analogous to example 5.2, using 1 g (2.4 mmol) of
methyl
(R)-3-(4-hydroxy-benzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl-
)propanoate and 500 mg (2.6 mmol) of
4-chloromethyl-2-methylquinoline, 740 mg (53%) of methyl
(R)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethox-
y)benzenesulfonylamino]propanoate are obtained in the form of a
solid.
12.6:
(R)-2-(4-Methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylm-
ethoxy)benzenesulfonyl-amino]propanoic acid
In a manner analogous to example 3.7, using 740 mg (1.3 mmol) of
methyl
(R)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethox-
y)benzenesulfonylamino]propanoate, 622 mg (86%) of
(R)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethox-
y)-benzenesulfonylamino]propanoic acid are obtained.
12.7:
(R)--N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylqui-
nolin-4-ylmethoxy)-benzenesulfonylamino]propionamide
In a manner analogous to example 3.8, using 620 mg (1.1 mmol) of
(R)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethox-
y)benzenesulfonylamino]propanoic acid, 465 mg (73%) of
(R)--N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-
-4-ylmethoxy)benzenesulfonylamino]propionamide are obtained in the
form of a white solid.
.sup.1H NMR (.delta., DMSO): 2.53 (m, 4H); 2.68 (s, 3H); 2.84 (s,
3H); 2.85 (m, 2H); 2.95-3.05 (m, 4H); 3.10 (m, 1H); 5.72 (s, 2H);
7.35 (d, J=8.8 Hz, 2H); 7.52 (m, 1H); 7.57-7.62 (m, 2H); 7.75-7.82
(m, 3H); 7.98 (d, J=8.4 Hz, 1H); 8.11 (d, J=8.16 Hz, 1H); 8.93 (s,
1H); 10.70 (s, 1H).
EXAMPLE 13
(S)--N-Hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2--
piperazin-1-ylpropionamide
13.1: Benzyl
4-{(S)-1-hydroxycarbamoyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfo-
nylamino]-ethyl}piperazine-1-carboxylate:
In a manner analogous to example 3.8, using 135 mg (0.2 mmol) of
benzyl
4-{(S)-1-carboxy-2-[4-(2-methylquinolin-4-ylmethoxybenzenesulfonylamino]e-
thyl}piperazine-1-carboxylate (prepared as described in 10.6), 115
mg (82%) of benzyl
4-{(S)-1-hydroxycarbamoyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfo-
nylamino]ethyl}piperazine-1-carboxylate are obtained in the form of
a white solid with a melting point of 162.degree. C.
13.2:
(S)--N-Hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylami-
no]-2-piperazin-1-ylpropionamide
90 mg (0.15 mmol) of benzyl
4-{(S)-1-hydroxycarbamoyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfo-
nylamino]ethyl}piperazine-1-carboxylate are placed in solution in 5
ml of dichloromethane and 5 ml of trifluoroacetic acid. The
reaction medium is then stirred at ambient temperature for 96 h.
After evaporation of the trifluoroacetic acid, the residue is taken
up with 5 ml of saturated aqueous solution of sodium hydrogen
carbonate and extracted with n-butanol. The organic phase is washed
with water and then with a saturated aqueous solution of sodium
chloride, dried over magnesium sulfate, filtered and concentrated
under vacuum. The crude product obtained is taken up in a 50/50
heptane/ethyl acetate mixture, stirred for 1 h and then filtered
and dried under vacuum. 50 mg (70%) of
(S)--N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-
-piperazin-1-ylpropionamide are obtained in the form of a beige
solid with a melting point of 225.degree. C.
.sup.1H NMR (.delta., DMSO): 2.35-2.45 (m, 4H); 2.67 (s, 3H); 2.70
(m, 4H); 2.80-3.00 (m, 2H); 3.15 (s, 1H); 5.72 (s, 2H); 7.35 (d,
J=8.6 Hz, 2H); 7.70-7.80 (m, 3H); 7.98 (d, J=8.4 Hz, 1H); 8.12 (d,
J=8.2 Hz, 1H).
EXAMPLE 14
(S)--N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin--
4-ylmethoxy)benzenesulfonylamino]propionamide hydrochloride
0.2 ml (1.3 mmol) of a solution of hydrochloric acid in isopropanol
having a concentration of 5-6N is added to a solution of 301 mg
(0.5 mmol) of
(S)--N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methy-
lquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide (prepared
as described in example 14) in 10 ml of isopropanol. After stirring
at ambient temperature for 1 h, the product precipitates. Through
filtration, 927 mg of
(S)--N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-
-4-ylmethoxy)benzenesulfonylamino]propionamide hydrochloride are
obtained in the form of a white powder. This solid is
recrystallized from a 30 ml/5 ml isopropanol/water mixture. 176 mg
(52%) of
(S)--N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-
-4-ylmethoxy)benzenesulfonylamino]propionamide are obtained in the
form of a white powder with a melting point of 209.degree. C.
.sup.1H NMR (.delta., DMSO): 2.67 (m, 4H); 2.87 (s, 3H); 2.93 (s,
3H); 3.00-3.15 (m, 4H); 3.22 (m, 1H); 3.35-3.90 (m, 2H); 5.94 (s,
2H); 7.42 (d, J=8.7 Hz, 2H); 7.64 (m, 1H); 7.83-7.90 (m, 3H); 7.98
(m, 1H); 8.05 (m, 1H); 8.30 (d, J=7.6 Hz; 1H); 8.38 (d, J=8.5 Hz,
1H); 9.00 (m, 1H); 10.75 (m, 1H).
EXAMPLE 15
tert-Butyl
3-{(4-[(S)-2-hydroxycarbamoyl-2-(4-methanesulfonylpiperazin-1-y-
l)ethylsulfamoyl]phenoxymethyl}-2-methylindole-1-carboxylate
di(trifluoroacetate)
15.1: tert-Butyl
3-{4-[(S)-2-(4-methanesulfonylpiperazin-1-yl)-2-methoxycarbonylethylsulfa-
moyl]-phenoxymethyl}-2-methylindole-1-carboxylate
In a manner analogous to example 11.1, using 400 mg (0.95 mmol) of
methyl
(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)-
propanoate (prepared as described in example 5.1) and 248 mg (0.95
mmol) of commercial tert-butyl
3-hydroxymethyl-2-methylindole-1-carboxylate, 326 mg (52%) of
tert-butyl
3-{4-[(S)-2-(4-methanesulfonylpiperazin-1-yl)-2-methoxycarbonylethylsulfa-
moyl]phenoxymethyl}-2-methylindole-1-carboxylate are obtained in
the form of a beige powder.
15.2: tert-Butyl
3-{4-[(S)-2-carboxy-2-(4-methanesulfonylpiperazin-1-yl)-ethylsulfamoyl]ph-
enoxy-methyl}-2-methylindole-1-carboxylate
In a manner analogous to example 3.7, using 325 mg (0.5 mmol) of
tert-butyl
3-{4-[(S)-2-(4-methanesulfonylpiperazin-1-yl)-2-methoxycarbonylethylsulfa-
moyl]phenoxymethyl}-2-methylindole-1-carboxylate, 179 mg (100%) of
tert-butyl
3-{4-[(S)-2-carboxy-2-(4-methanesulfonylpiperazin-1-yl)ethylsulfamoyl]phe-
noxymethyl}-2-methylindole-1-carboxylate are obtained in the form
of a yellow powder.
15.3: tert-Butyl
3-{4-[(S)-2-hydroxycarbamoyl-2-(4-methanesulfonylpiperazin-1-yl)ethylsulf-
amoyl]-phenoxymethyl}-2-methylindole-1-carboxylate
di(trifluoroacetate)
45 mg (0.3 mmol) of O-tert-butyldimethylsilylhydroxylamine in
solution in 1 ml of dimethylformamide are added to a solution of
179 mg (0.3 mmol) of tert-butyl
3-{4-[(S)-2-carboxy-2-(4-methanesulfonylpiperazin-1-yl)ethylsulfamoyl]phe-
noxymethyl}-2-methyl-indole-1-carboxylate, 41 mg (0.3 mmol) of
1-hydroxybenzotriazole and 58 mg (0.3 mmol) of
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride in 3 ml
of dimethylformamide. The reaction mixture is stirred at ambient
temperature for 18 h. After the addition of water and then
extraction with ethyl acetate, the organic phases are combined,
washed with a saturated solution of sodium hydrogen carbonate and
then dried over sodium sulfate, filtered and evaporated. The
residue is purified by preparative HPLC (Gemini C6 phenyl column,
150.times.3 mm, 3 .mu.m; UV detector: 190-420 nm; flow rate: 0.3
ml/mn; solvent A: CH.sub.3CN+0.02% trifluoroacetic acid; solvent B:
water+0.02% trifluoroacetic acid).
Gradient:
TABLE-US-00001 Time Composition 0.0 min A = 5% B = 95% 20.0 min A =
98% B = 2% 30.0 min A = 98% B = 2% Retention time: 14.6 min, M + 1
= 666.1.
After concentration of the various fractions, 21 mg (10%) of
tert-butyl
3-{4-[(S)-2-hydroxycarbamoyl-2-(4-methanesulfonylpiperazin-1-yl)ethylsulf-
amoyl]phenoxymethyl}-2-methylindole-1-carboxylate
di(trifluoroacetate) are obtained.
EXAMPLE 16
(S)--N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-ylmeth-
oxy)benzenesulfonylamino]propionamide
16.1: Methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-ylmethoxy)benzen-
esulfonyl-amino]propanoate
In a manner analogous to example 5.2, using 440 mg (2.5 mmol) of
4-chloromethylquinoline and 950 mg (2.2 mmol) of methyl
(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)-
propanoate (prepared as described in 5.1), 550 mg (43%) of methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-ylmethoxy)benzen-
esulfonylamino]propanoate are obtained in the form of a colorless
oil.
16.2:
(S)-2-(4-Methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-ylmethoxy)b-
enzenesulfonylamino]-propanoic acid
In a manner analogous to example 3.7, using 550 mg (1.0 mmol) of
methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-ylmethoxy)benzen-
esulfonylamino]propanoate, 450 mg (83%)
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-ylmethoxy)benzen-
esulfonylamino]-propanoic acid are obtained in the form of a white
solid.
16.3:
(S)--N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4--
ylmethoxy)benzenesulfonyl-amino]propionamide
In a manner analogous to example 3.8, using 450 mg (0.8 mmol) of
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-ylmethoxy)benzen-
esulfonylamino]propanoic acid, 260 mg (56%) of
(S)--N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-ylmet-
hoxy)benzenesulfonylamino]propionamide are obtained in the form of
a white solid with a melting point of 180.degree. C.
.sup.1H NMR (.delta., DMSO): 2.52-2.54 (m, 4H); 2.84 (s, 3H); 2.87
(m, 1H); 2.97 (m, 1H); 2.98-3.05 (m, 4H), 3.11 (t, J=7 Hz, 1H);
5.78 (s, 2H); 7.34 (d, J=8.8 Hz, 2H); 7.52 (m, 1H); 7.66-7.72 (m,
2H); 7.78-7.84 (m, 3H); 8.10 (d, J=8.3 Hz, 1H); 8.19 (d, J=8.2 Hz,
1H); 8.93 (s, 1H); 8.94 (s, 1H); 10.67 (s, 1H).
EXAMPLE 17
(S)-2-(4-Benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethox-
y)-benzenesulfonylamino]propionamide
17.1: Sodium salt of
4-(2-methylquinolin-4-ylmethoxy)benzenesulfonic acid
100 g (438 mmol) of 4-chloromethyl-2-methylquinoline hydrochloride
are added to a solution of 77 g (395 mmol) of the sodium salt of
4-hydroxybenzenesulfonic acid and of 84 ml (84 mmol) of an aqueous
solution of sodium hydroxide, having a concentration of 1M, in 800
ml of isopropanol. The reaction medium is heated at 70.degree. C.
for 5 h and then at 40.degree. C. for 18 h.
After evaporation of the isopropanol, the product obtained is
filtered, rinsed with isopropanol and with diethyl ether and then
dried under vacuum. 114 g (75%) of the sodium salt of
4-(2-methylquinolin-4-ylmethoxy)benzenesulfonic acid are obtained
in the form of a white solid.
17.2: 4-(2-Methylquinolin-4-ylmethoxy)benzenesulfonyl chloride
76 g (216 mmol) of the sodium salt of
4-(2-methylquinolin-4-ylmethoxy)benzenesulfonic acid in 500 ml of
dimethylformamide are added dropwise to a solution of 55 ml (649
mmol) of oxalyl chloride in 100 ml of dichloromethane, cooled
beforehand to -10.degree. C. After the addition, the reaction
medium is stirred at ambient temperature for 18 h. The reaction
medium is then poured into 1 l of ice and then extracted with ethyl
acetate. The organic phases are combined, washed with water and
then with a saturated aqueous solution of sodium chloride, dried
over magnesium sulfate, filtered and concentrated under vacuum. 77
g (92%) of 4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride
hydrochloride are obtained in the form of a beige solid.
17.3: Benzylbis(2-chloroethyl)amine
21 g (152 mmol) of potassium carbonate and then 8 ml (67 mmol) of
benzyl bromide are added to a solution of 10 g (56 mmol) of
bis(2-chloroethyl)amine hydrochloride in 130 ml of acetonitrile,
and then the reaction medium is heated at 60.degree. C. for 24 h.
After filtration, the filtrate is concentrated under vacuum. The
crude residue is purified by chromatography on silica gel, elution
being carried out with a 90/10 heptane/ethyl acetate mixture, to
give 8.5 g (65%) of benzylbis(2-chloroethyl)amine.
17.4: Methyl
(S)-2-(4-benzylpiperazin-1-yl)-3-tert-butoxycarbonylaminopropanoate
A solution of 5.9 g (23 mmol) of commercial methyl
(S)-2-amino-3-tert-butoxycarbonylamino-propanoate hydrochloride and
of 9.6 g (23 mmol) of benzylbis(2-chloroethyl)amine in 50 ml of
N,N-diisopropylethylamine is heated at 127.degree. C. for 3 h 30.
After evaporation of the N,N-diisopropylethylamine, the reaction
medium is hydrolyzed and then extracted with ethyl acetate. The
organic phase is washed with an aqueous solution of sodium
hydroxide having a concentration of 1N, and with water, and then
dried over magnesium sulfate, filtered and concentrated under
vacuum. The crude product obtained is purified by chromatography on
silica gel, elution being carried out with a 50/50 heptane/ethyl
acetate mixture. 8.9 g (64%) of methyl
(S)-2-(4-benzylpiperazin-1-yl)-3-tert-butoxycarbonylaminopropanoat-
e are obtained in the form of a yellow oil.
17.5: Methyl (S)-3-amino-2-(4-benzylpiperazin-1-yl)propanoate
trihydrochloride
8.9 g (23.5 mmol) of methyl
(S)-2-(4-benzylpiperazin-1-yl)-3-tert-butoxycarbonylaminopropanoate
are placed in solution in 60 ml of methanol and in 20 ml of
isopropanolic hydrochloric acid having a concentration of 5-6N. The
reaction medium is stirred at 40.degree. C. for 18 h and then
concentrated under vacuum. 9.0 g (100%) of methyl
(S)-3-amino-2-(4-benzylpiperazin-1-yl)propanoate trihydrochloride
are obtained in the form of a beige solid.
17.6: Methyl
(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzene-
sulfonyl-amino]propanoate
In a manner analogous to example 3.6, using 1.0 g (2.6 mmol) of
methyl (S)-3-amino-2-(4-benzylpiperazin-1-yl)propanoate
trihydrochloride and 1.1 g (2.8 mmol) of
4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride in
hydrochloride form, 750 mg (50%) of methyl
(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzene-
sulfonylamino]propanoate are obtained in the form a beige
solid.
17.7:
(S)-2-(4-Benzylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)be-
nzenesulfonylamino]-propanoic acid
In a manner analogous to example 3.7, using 750 mg (1.3 mmol) of
methyl
(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzene-
sulfonylamino]propanoate, 680 mg (93%) of
(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzene-
sulfonylamino]propanoic acid are obtained in the form of a white
solid.
17.8:
(S)-2-(4-Benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-yl-
methoxy)benzenesulfonylamino]propionamide
In a manner analogous to example 3.8, using 680 mg (1.2 mmol) of
(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzene-
sulfonylamino]propanoic acid, 250 mg (36%) of
(S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmetho-
xy)benzenesulfonylamino]propion-amide are obtained in the form of a
white solid with a melting point of 188.degree. C.
.sup.1H NMR (.delta., DMSO): 2.33 (m, 4H); 2.49 (m, 4H); 2.73 (s,
3H); 2.80-2.90 (m, 1H); 3.00-3.10 (m, 2H); 2.46 (m, 2H); 5.77 (s,
2H); 7.25-7.40 (m, 7H); 7.50 (m, 1H); 7.61-7.67 (m, 2H); 7.78-7.85
(m, 3H); 8.04 (d, J=8 Hz, 1H); 8.17 (d, J=8.2 Hz, 1H); 8.95 (s,
1H); 10.65 (s, 1H).
EXAMPLE 18
(S)-2-[4-(4-Fluorobenzyl)piperazin-1-yl]-N-hydroxy-3-[4-(2-methylquinolin--
4-ylmethoxy)benzenesulfonylamino]propionamide
18.1: Bis(2-chloroethyl)(4-fluorobenzyl)amine
In a manner analogous to example 17.3, using 5 g (28 mmol) of
bis(2-chloroethyl)amine hydrochloride and 3.8 ml (31 mmol) of
1-bromomethyl-4-fluorobenzene, 6.9 g (98%) of
bis(2-chloroethyl)(4-fluorobenzyl)amine are obtained.
18.2: Methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(4-fluorobenzyl)piperazin-1-yl]propan-
oate
In a manner analogous to example 17.4, using 7.1 g (28 mmol) of
methyl (S)-2-amino-3-tert-butoxycarbonylaminopropanoate
hydrochloride and 6.9 g (28 mmol) of
bis(2-chloroethyl)(4-fluorobenzyl)amine, 5.3 g (48%) of methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(4-fluorobenzyl)piperazin-1-yl-
]propanoate are obtained in the form of an oil.
18.3: Methyl
(S)-3-amino-2-[4-(4-fluorobenzyl)piperazin-1-yl]propanoate
trihydrochloride
In a manner analogous to example 17.5, using 5.3 g (13.4 mmol) of
methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(4-fluorobenzyl)piperazin-1-yl]propan-
oate, 5.4 g (100%) of methyl
(S)-3-amino-2-[4-(4-fluorobenzyl)piperazin-1-yl]propanoate
trihydrochloride are obtained in the form of a beige solid.
18.4: Methyl
(S)-2-[4-(4-fluorobenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmetho-
xy)benzenesulfonylamino]propanoate
In a manner analogous to example 3.6, using 1.5 g (3.7 mmol) of
methyl (S)-3-amino-2-[4-(4-fluorobenzyl)piperazin-1-yl]propanoate
trihydrochloride and 1.6 g (4.1 mmol) of
4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride
hydrochloride (prepared as described in 17.2), 1.0 g (46%) of
methyl
(S)-2-[4-(4-fluorobenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmetho-
xy)benzenesulfonyl-amino]propanoate is obtained in the form of a
white solid.
18.5:
(S)-2-[4-(4-fluorobenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-yl-
methoxy)benzenesulfonyl-amino]propanoic acid
In a manner analogous to example 3.7, using 1.1 g (1.7 mmol) of
methyl
(S)-2-[4-(4-fluorobenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmetho-
xy)benzenesulfonylamino]propanoate, 1.0 g (100%) of
(S)-2-[4-(4-fluorobenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmetho-
xy)benzene-sulfonylamino]propanoic acid are obtained in the form of
a white solid.
18.6:
(S)-2-[4-(4-Fluorobenzyl)piperazin-1-yl]-N-hydroxy-3-[4-(2-methylqui-
nolin-4-ylmethoxy)benzenesulfonylamino]propionamide
In a manner analogous to example 3.8, using 990 mg (1.7 mmol) of
(S)-2-[4-(4-fluorobenzyl)-piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmeth-
oxy)benzenesulfonylamino]propanoic acid, 330 mg (33%) of
(S)-2-[4-(4-fluorobenzyl)piperazin-1-yl]-N-hydroxy-3-[4-(2-methylquinolin-
-4-ylmethoxy)-benzenesulfonylamino]propionamide are obtained in the
form of a white solid with a melting point of 180.degree. C.
.sup.1H NMR (.delta., DMSO): 2.20-2.30 (m, 4H); 2.35-2.45 (m, 4H);
2.66 (s, 3H); 2.72-2.80 (m, 1H); 2.87-3.00 (m, 2H); 3.38 (s, 2H);
5.70 (s, 2H); 7.10 (t, J=8.8 Hz, 2H); 7.26-7.33 (m, 4H); 7.56-7.60
(m, 2H); 7.73-7.78 (m, 3H); 7.97 (d, J=8.4 Hz, 1H); 8.10 (d, J=8.2
Hz, 1H).
EXAMPLE 19
(S)-2-(4-ethyl-piperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-yl-metho-
xy)benzenesulfonylamino]propionamide
19.1: bis(2-Chloroethyl)ethylamine
24 ml (330 mmol) of thionyl chloride are added dropwise to a
solution of 20 g (150 mmol) of
2-[ethyl(2-hydroxyethyl)amino]ethanol in 200 ml of dichloromethane
cooled beforehand to 0.degree. C., and then the reaction medium is
stirred at ambient temperature for 20 h. After the addition of a
saturated aqueous solution of sodium hydrogen carbonate, the
product is extracted with dichloromethane. The organic phase
obtained is then washed with water, dried over magnesium sulfate,
filtered and concentrated under vacuum. 19.5 g (76%) of
bis(2-chloroethyl)ethylamine are obtained in the form of an
oil.
19.2: Methyl
(S)-3-tert-butoxycarbonylamino-2-(4-ethylpiperazin-1-yl)propanoate
A solution of 5.0 g (19.6 mmol) of commercial methyl
(S)-2-amino-3-tert-butoxycarbonylamino-propanoate hydrochloride and
3.3 g (19.6 mmol) of bis(2-chloroethyl)ethylamine in 50 ml of
N,N-diisopropylethylamine is heated at 127.degree. C. for 5 h.
After evaporation of a maximum amount of diisopropylethylamine, the
reaction medium is diluted with ethyl acetate and washed with an
aqueous solution of sodium hydroxide having a concentration of 1N.
The organic phase obtained is then washed with water, dried over
magnesium sulfate, filtered and concentrated under vacuum. The
crude product obtained is purified by chromatography on silica gel,
elution being carried out with a 30/70 heptane/ethyl acetate
mixture. 2.5 g (40%) of methyl
(S)-3-tert-butoxycarbonylamino-2-(4-ethylpiperazin-1-yl)propanoate
are obtained in the form of an oil.
19.3: Methyl (S)-3-amino-2-(4-ethylpiperazin-1-yl)propanoate
trihydrochloride
2.5 g (7.9 mmol) of methyl
(S)-3-tert-butoxycarbonylamino-2-(4-ethylpiperazin-1-yl)propanoate
are placed in 20 ml of methanol and 10 ml of isopropanolic
hydrochloric acid having a concentration of 5-6N. The reaction
medium is heated at 40.degree. C. for 3 h and then evaporated to
dryness. The residue is taken up in 50 ml of ethanol, stirred for 1
h at ambient temperature and then filtered. 1.4 g (54%) of methyl
(S)-3-amino-2-(4-ethylpiperazin-1-yl)propanoate trihydrochloride
are obtained in the form of a beige solid.
19.4: Methyl
(S)-2-(4-ethylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenes-
ulfonylamino]-propanoate
In a manner analogous to example 3.6, using 700 mg (2.1 mmol) of
methyl (S)-3-amino-2-(4-ethylpiperazin-1-yl)propanoate
trihydrochloride and 900 mg (2.3 mmol) of
4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride
hydrochloride (prepared as described in 17.2), 740 mg (67%) of
methyl
(S)-2-(4-ethylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenes-
ulfonylamino]-propanoate are obtained in the form of a white
solid.
19.5:
(S)-2-(4-Ethylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)ben-
zenesulfonylamino]-propanoic acid
In a manner analogous to example 3.7, using 740 mg (1.4 mmol) of
methyl
(S)-2-(4-ethylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenes-
ulfonylamino]propanoate, 630 mg (87%) of
(S)-2-(4-ethylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenes-
ulfonylamino]propanoic acid are obtained in the form of a white
solid.
19.6:
(S)-2-(4-Ethylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylm-
ethoxy)benzenesulfonyl-amino]propionamide
In a manner analogous to example 3.8, using 630 mg (1.2 mmol) of
(S)-2-(4-ethylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenes-
ulfonylamino]propanoic acid, 60 mg (8%) of
(S)-2-(4-ethylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethox-
y)benzenesulfonylamino]propion-amide are obtained in the form of a
white solid with a melting point of 150.degree. C.
.sup.1H NMR (.delta., DMSO): 2.49 (s, 3H); 2.55-2.65 (m, 2H); 2.69
(s, 3H); 2.70-2.90 (m, 6H); 2.90-3.00 (m, 2H); 3.13 (t, J=7.3 Hz,
1H); 3.20-3.35 (m, 2H); 3.36 (s, 2H); 5.72 (s, 2H); 7.35 (d, J=8.9
Hz, 2H); 7.58-7.62 (m, 3H); 7.74-7.81 (m, 3H); 7.98 (d, J=7.9 Hz,
1H); 8.12 (d, J=8.3 Hz, 1H); 9.03 (s, 1H), 10.82 (s, 1H).
EXAMPLE 20
(S)--N-Hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2--
[4-(4-trifluoromethylbenzyl)piperazin-1-yl]propionamide
20.1: bis-(2-Chloroethyl)(4-trifluoromethylbenzyl)amine
In a manner analogous to example 32.3, using 5.0 g (28 mmol) of
bis(2-chloroethyl)amine hydrochloride and 7.4 g (31 mmol) of
1-bromomethyl-4-trifluoromethylbenzene, 5 g (59%) of a
bis(2-chloroethyl)(4-trifluoromethylbenzyl)amine mixture are
obtained in the form of a colorless oil.
20.2: Methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(4-trifluoromethylbenzyl)piperazin-1--
yl]propanoate
A solution of 4.2 g (16.5 mmol) of methyl
(S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride and
4.95 g (16.5 mmol) of
bis(2-chloroethyl)(4-trifluoromethylbenzyl)amine in 25 ml of
N,N-diisopropylethylamine is heated at 127.degree. C. for 6 h.
After evaporation of a maximum amount of diisopropylethylamine, the
reaction medium is diluted with ethyl acetate and washed with an
aqueous solution of sodium hydroxide having a concentration of 1N.
The organic phase obtained is washed with water, dried over
magnesium sulfate, filtered and concentrated under vacuum. The
crude residue is purified by chromatography on silica gel, elution
being carried out with a 60/40 heptane/ethyl acetate mixture. 4.0 g
(55%) of methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(4-trifluoromethylbenzyl)-piperazin-1-
-yl]propanoate are obtained in the form of an oil.
20.3: Methyl
(S)-3-amino-2-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]propanoate
trihydrochloride
In a manner analogous to example 17.5, using 4 g (9.1 mmol) of
methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(4-trifluoromethylbenzyl)piperazin-1--
yl]propanoate, 3.8 g (93%) of methyl
(S)-3-amino-2-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]propanoate
are obtained in the form of a beige solid.
20.4: Methyl
(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-trif-
luoromethyl-benzyl)piperazin-1-yl]propanoate
In a manner analogous to example 3.6, using 1.0 g (2.2 mmol) of
methyl
(S)-3-amino-2-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]propanoate
trihydrochloride and 1.2 g (3.1 mmol) of
4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride
hydrochloride (prepared as described in example 17.2), 910 mg (65%)
of methyl
(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzene-sulfonylamino]-2-[4-(4-tri-
fluoromethylbenzyl)piperazin-1-yl]propanoate are obtained in the
form of a white solid.
20.5:
(S)-3-[4-(2-Methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-
-trifluoromethylbenzyl)-piperazin-1-yl]propanoic acid
In a manner analogous to example 3.7, using 910 mg (1.4 mmol) of
methyl
(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-trif-
luoromethylbenzyl)piperazin-1-yl]-propanoate, 790 mg (88%) of
(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-trif-
luoromethylbenzyl)-piperazin-1-yl]propanoic acid are obtained in
the form of a white solid.
20.6:
(S)--N-Hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylami-
no]-2-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]propionamide
In a manner analogous to example 3.8, using 790 mg (1.2 mmol) of
(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-trif-
luoromethylbenzyl)piperazin-1-yl]propanoic acid, 550 mg (68%) of
(S)--N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-
-[4-(4-trifluoro-methylbenzyl)piperazin-1-yl]propionamide are
obtained in the form of a white solid with a melting point of
148.degree. C.
.sup.1H NMR (.delta., DMSO): 2.21 (m, 4H); 2.38 (m, 4H); 2.58 (s,
3H); 2.69-2.75 (m, 1H); 2.85-2.93 (m, 1H); 2.93-2.98 (m, 1H); 3.42
(s, 2H); 5.63 (s, 2H); 7.25 (d, J=9 Hz, 2H); 7.40 (d, J=8 Hz, 3H);
7.47-7.53 (m, 2H); 7.57 (d, J=8.1 Hz, 2H); 7.65-7.72 (m, 3H); 7.90
(d, J=7.9 Hz, 1H); 8.03 (d, J=7.8 Hz, 1H); 8.83 (s, 1H), 10.56 (s,
1H).
EXAMPLE 21
(S)--N-hydroxy-2-[4-(4-methylbenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-
-4-ylmethoxy)benzenesulfonylamino]propionamide
21.1: bis(2-Chloroethyl)(4-methylbenzyl)amine
In a manner analogous to example 17.3, using 5.0 g (28 mmol) of
bis(2-chloroethyl)amine hydrochloride and 5.7 g (31 mmol) of
1-bromomethyl-4-methylbenzene, 4.9 g (71%) of
bis(2-chloroethyl)(4-methylbenzyl)amine are obtained.
21.2: Methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(4-methylbenzyl)piperazin-1-yl]propan-
oate
In a manner analogous to example 17.4, using 5.1 g (20 mmol) of
commercial methyl (S)-2-amino-3-tert-butoxycarbonylaminopropanoate
hydrochloride and 4.9 g (20 mmol) of
bis(2-chloroethyl)(4-methylbenzyl)amine, 4.1 g (53%) of methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(4-methylbenzyl)piperazin-1-yl]propan-
oate are obtained in the form of an oil.
21.3: Methyl
(S)-3-amino-2-[4-(4-methylbenzyl)piperazin-1-yl]propanoate
trihydrochloride
In a manner analogous to example 19.3, using 4.1 g (10.5 mmol) of
methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(4-methylbenzyl)piperazin-1-yl]propan-
oate, 3.95 g (94%) of methyl
(S)-3-amino-2-[4-(4-methylbenzyl)piperazin-1-yl]propanoate
trihydrochloride are obtained in the form of a cream solid.
21.4: Methyl
(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-meth-
ylbenzyl)-piperazin-1-yl]propanoate
In a manner analogous to example 3.6, using 1.0 g (2.5 mmol) of
methyl (S)-3-amino-2-[4-(4-methylbenzyl)piperazin-1-yl]propanoate
trihydrochloride and 1.3 g (3.5 mmol) of
4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride
hydrochloride (prepared as described in example 17.2), 950 mg (63%)
of methyl
(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-meth-
ylbenzyl)piperazin-1-yl]propanoate are obtained in the form of a
white solid.
21.5:
(S)-2-[4-(4-Methylbenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-yl-
methoxy)benzenesulfonylamino]propanoic acid
In a manner analogous to example 3.7, using 950 mg (1.6 mmol) of
methyl
(S)-2-[4-(4-methylbenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmetho-
xy)benzenesulfonylamino]propanoate, 880 mg (95%) of
(S)-2-[4-(4-methylbenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmetho-
xy)benzenesulfonylamino]propanoic acid are obtained in the form of
a cream solid.
21.6:
(S)--N-Hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylami-
no]-2-[4-(4-methylbenzyl)piperazin-1-yl]propionamide
In a manner analogous to example 3.8, using 880 mg (1.5 mmol) of
(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-meth-
ylbenzyl)piperazin-1-yl]propanoic acid, 150 mg (17%) of
(S)--N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-
-[4-(4-methylbenzyl)-piperazin-1-yl]propionamide are obtained in
the form of a white solid with a melting point of 170.degree.
C.
.sup.1H NMR (.delta., DMSO): 2.25 (m, 4H); 2.25 (s, 3H); 2.43 (m,
4H); 2.67 (s, 3H); 2.80 (m, 1H); 2.95-3.05 (m, 2H); 3.37 (m, 2H);
5.71 (s, 2H); 7.10 (q, J=8 Hz, 4H); 7.33 (d, J=8.9 Hz, 2H); 7.43
(m, 1H); 7.56-7.61 (m, 2H); 7.73-7.79 (m, 3H); 7.98 (d, J=8.3 Hz,
1H); 8.11 (d, J=8.2 Hz, 1H); 8.89 (s, 1H); 10.59 (s, 1H).
EXAMPLE 22
(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-N-hydroxy-2-(4-m-
ethanesulfonylpiperazin-1-yl)propionamide
22.1: Benzoisoxazol-3-ylmethanol
589 mg (3.0 mmol) of ethyl 1.2-benzoisoxazole-3-carboxylate in
solution in 10 ml of tetrahydrofuran are added to a suspension of
129 mg (3.5 mmol) of lithium aluminum hydride in 5 ml of
tetrahydrofuran. The reaction mixture is stirred for one hour at
60.degree. C. and then treated by adding 2 ml of methanol dropwise,
filtered through celite and rinsed with ethyl acetate. The organic
phases are combined, dried over sodium sulfate and evaporated. The
residue obtained is purified by chromatography on silica gel,
elution being carried out with a 60/40 heptane/ethyl acetate
mixture. 180 mg (39%) of benzoisoxazol-3-ylmethanol are obtained in
the form of a white solid.
22.2: Methyl
(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-2-(4-methanesul-
fonyl-piperazin-1-yl)propanoate
In a manner analogous to example 11.1, using 494 mg (1.2 mmol) of
methyl
(S)-3-(4-hydroxy-benzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl-
)propanoate (prepared as described in 5.1) and 175 mg (1.2 mmol) of
benzoisoxazol-3-ylmethanol, 459 mg (71%) of methyl
(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-2-(4-methanesul-
fonylpiperazin-1-yl)propanoate are obtained in the form of an
oil.
22.3:
(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-2-(4-metha-
nesulfonylpiperazin-1-yl)propanoic acid
In a manner analogous to example 3.7, using 458 mg (0.8 mmol) of
methyl
(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-2-(4-methanesul-
fonylpiperazin-1-yl)propanoate, 283 mg (63%) of
(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-2-(4-methanesul-
fonylpiperazin-1-yl)propanoic acid are obtained in the form of a
white solid.
22.4:
(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-N-hydroxy--
2-(4-methanesulfonyl-piperazin-1-yl)propionamide
In a manner analogous to example 3.8, using 283 mg (0.5 mmol) of
(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-2-(4-ethanesulf-
onylpiperazin-1-yl)propanoic acid, 231 mg (80%) of
(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-N-hydroxy-2-(4--
methanesulfonyl-piperazin-1-yl)propionamide are obtained in the
form of a beige solid with a melting point of 107.degree. C.
.sup.1H NMR (.delta., DMSO): 2.53-2.55 (m, 4H); 2.88 (s, 3H);
2.90-2.93 (m, 2H); 3.00-3.10 (m, 4H); 3.13 (t, J=6.9 Hz, 1H); 5.77
(s, 2H); 7.35 (d, J=8.8 Hz, 2H); 7.49 (t, J=7.5 Hz, 1H); 7.57 (m,
1H); 7.75 (t, J=7.4 Hz, 1H); 7.78-7.87 (m, 3H); 8.01 (d, J=8 Hz,
1H); 8.96 (m, 1H); 10.67 (m, 1H).
EXAMPLE 23
(S)--N-hydroxy-2-(4-isobutyrylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylm-
ethoxy)-benzenesulfonylamino]propionamide
23.1: Methyl
(S)-3-tert-butoxycarbonylamino-2-piperazin-1-ylpropanoate
2 g (25% by weight) of palladium-on-carbon at 10% are added to a
solution of 8 g (21 mmol) of
methyl(S)-2-(4-benzylpiperazin-1-yl)-3-tert-butoxycarbonylaminopropanoate
(prepared as described in example 17.4) in 120 ml of ethanol,
degassed beforehand under a nitrogen stream. The reaction medium is
then placed under a hydrogen atmospheric pressure for 24 h and then
filtered through celite and thoroughly rinsed with dichloromethane.
After concentration under vacuum, 6.1 g (100%) of methyl
(S)-3-tert-butoxycarbonylamino-2-piperazin-1-ylpropanoate are
obtained.
23.2: Methyl
(S)-3-tert-butoxycarbonylamino-2-(4-isobutyrylpiperazin-1-yl)propanoate
1.2 ml (8.3 mmol) of triethylamine and then 0.8 ml (7.6 mmol) of
isobutyryl chloride are added to a solution of 2.0 g (6.9 mmol) of
methyl (S)-3-tert-butoxycarbonylamino-2-piperazin-1-ylpropanoate in
20 ml of dichloromethane, cooled beforehand to 0.degree. C. After
stirring at ambient temperature for 1 h 30, water is added. The
reaction medium is extracted with dichloromethane. The organic
phase is washed with water, dried over magnesium sulfate, filtered
and concentrated under vacuum. The crude residue obtained is
purified by chromatography on silica gel, elution being carried out
with a 50/50 heptane/ethyl acetate mixture. 2.0 g (81%) of methyl
(S)-3-tert-butoxycarbonylamino-2-(4-isobutyryl-piperazin-1-yl)propanoate
are obtained in the form of a colorless oil.
23.3:
(S)-3-tert-butoxycarbonylamino-2-(4-isobutyrylpiperazin-1-yl)propano-
ic acid
10 ml (10 mmol) of an aqueous solution of lithium hydroxide having
a concentration of 1N are added to a solution of 2.0 g (5.6 mmol)
of methyl
(S)-3-tert-butoxycarbonylamino-2-(4-isobutyrylpiperazin-1-yl)propanoate
in 40 ml of tetrahydrofuran and 8 ml of water, and then the
reaction medium is stirred at ambient temperature for 20 h. After
the addition of an aqueous solution of acetic acid having a
concentration of 1N, the product is extracted with n-butanol. The
organic phase is dried over magnesium sulfate, filtered and
concentrated under vacuum, 1.5 g (78%) of
(S)-3-tert-butoxycarbonylamino-2-(4-isobutyrylpiperazin-1-yl)propanoic
acid are obtained in the form of a white solid.
23.4: tert-Butyl
[(S)-2-allyloxycarbamoyl-2-(4-isobutylylpiperazin-1-yl)ethyl]carbamate
1.4 g (4.4 mmol) of
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumtetrafluoroborate
and then 2.3 ml (13.1 mmol) of diisopropylethylamine are added to a
solution of 1.5 g (4.4 mmol) of
(S)-3-tert-butoxycarbonylamino-2-(4-isobutyrylpiperazin-1-yl)propanoic
acid in 20 ml of dimethylformamide. After stirring at ambient
temperature for 15 min, a solution of 500 mg (4.6 mmol) of
O-allylhydroxylamine hydrochloride and of 0.8 ml (4.6 mmol) of
diisopropylethylamine in 10 ml of dimethylformamide is added. The
reaction medium is stirred at ambient temperature for 20 h,
hydrolyzed with a saturated aqueous solution of sodium hydrogen
carbonate, and then diluted with ethyl acetate. The organic phase
is washed with a saturated aqueous solution of sodium chloride,
dried over magnesium sulfate, filtered and concentrated under
vacuum, 1.45 g (83%) of tert-butyl
[(S)-2-allyloxycarbamoyl-2-(4-isobutyrylpiperazin-1-yl)ethyl]carbamate
are obtained in the form of a colorless oil.
23.5:
(S)--N-allyloxy-3-amino-2-(4-isobutyrylpiperazin-1-yl)propionamide
dihydrochloride
In a manner analogous to example 19.3, using 1.45 g (3.6 mmol) of
tert-butyl
[(S)-2-allyloxycarbamoyl-2-(4-isobutyrylpiperazin-1-yl)ethyl]carbamate,
1.4 g (100%) of
(S)--N-allyloxy-3-amino-2-(4-isobutyrylpiperazin-1-yl)propionamide
dihydrochloride are obtained in the form of a white solid.
23.6:
(S)--N-allyloxy-2-(4-isobutyrylpiperazin-1-yl)-3-[4-(2-methylquinoli-
n-4-ylmethoxy)benzene-sulfonylamino]propionamide
1.9 g (5.1 mmol) of 4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl
chloride hydrochloride (prepared as described in 32.2) are added to
a solution of 1.3 g (3.6 mmol) of
(S)--N-allyloxy-3-amino-2-(4-isobutyrylpiperazin-1-yl)propionamide
dihydrochloride, 2.0 ml (14.5 mmol) of triethylamine in 15 ml of
dichloromethane and 15 ml of dimethylformamide, cooled beforehand
to 0.degree. C. The reaction medium is then stirred at from
0.degree. C. to ambient temperature over the course of 3 h. After
the addition of water, the reaction medium is extracted with
dichloromethane. The organic phase is washed with a saturated
aqueous solution of sodium hydrogen carbonate and with water, dried
over magnesium sulfate, filtered and concentrated.
The crude residue obtained is purified by silica column
chromatography, elution being carried out with a 97/3
dichloromethane/methanol mixture. 900 mg (41%) of
(S)--N-allyloxy-2-(4-isobutyrylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-y-
lmethoxy)benzenesulfonylamino]propionamide are obtained in the form
of a white solid.
23.7:
(S)--N-hydroxy-2-(4-isobutyrylpiperazin-1-yl)-3-[4-(2-methylquinolin-
-4-ylmethoxy)-benzenesulfonylamino]propionamide
33 mg (0.06 mmol) of tetrakis(triphenylphosphine)palladium and then
920 mg (6.6 mmol) of potassium carbamate are added to a solution of
670 mg (1.1 mmol) of
(S)--N-allyloxy-2-(4-isobutyrylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-y-
lmethoxy)benzenesulfonylamino]propionamide in 15 ml of methanol and
then the reaction medium is refluxed for 8 h. After the addition of
ethyl acetate, the reaction medium is washed with a saturated
aqueous solution of sodium hydrogen carbonate. The organic phase is
then washed with water, dried over magnesium sulfate. filtered and
concentrated. The crude product is taken up in 6 ml of ethanol and
12 ml of water and then heated at 80.degree. C. until
solubilization occurs. After cooling, crystallization is initiated
by evaporation of a minimum amount of ethanol. 120 mg of product
are obtained by filtration and are purified by preparative thin
layer chromatography on silica, elution being carried out with a
97/3 dichloromethane/methanol mixture. 20 mg (3%) of
(S)--N-hydroxy-2-(4-isobutyrylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-yl-
-methoxy)benzenesulfonylamino]propionamide are finally obtained in
the form of a beige solid.
.sup.1H NMR (.delta., DMSO): 0.84 (s, 3H); 0.85 (s, 3H); 2.30-2.44
(m, 2H); 2.52 (m, 2H); 2.67 (s, 3H); 2.77 (m, 1H); 2.85 (m, 2H);
2.95 (m, 1H); 3.35 (m, 4H); 5.71 (s, 2H); 7.33 (d, J=8.9 Hz, 2H);
7.43 (m, 1H); 7.55-7.62 (m, 2H); 7.72-7.82 (m, 3H); 7.98 (d, J=8.4
Hz, 1H); 8.11 (d, J=8.2 Hz, 1H); 8.96 (m, 1H); 10.67 (m, 1H).
EXAMPLE 24
(S)--N-hydroxy-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-l]-3-[4-(2-met-
hylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide
24.1: Methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(2-methylpropane-1-sulfonyl)piperazin-
-1-yl]propanoate
479 mg (3.0 mmol) of 2-methylpropane-1-sulfonyl chloride are added
to a solution of 800 mg (2.8 mmol) of methyl
(S)-3-tert-butoxycarbonylamino-2-piperazin-1-ylpropanoate (prepared
as described in example 23.1) and 775 .mu.l (5.5 mmol) of
triethylamine in 8 ml of dichloromethane, cooled beforehand to
0.degree. C. The reaction medium is stirred at ambient temperature
for 18 h and then water is added and the medium is extracted with
dichloromethane. The organic phase is washed with water, dried over
magnesium sulfate, filtered and concentrated. The residue obtained
is purified by chromatography on silica gel, elution being carried
out with a 5/5 heptane/ethyl acetate mixture. 785 mg (71%) of
methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(2-methylpropane-1-sulfonyl)piperazin-
-1-yl]propanoate are obtained in the form of a colorless oil.
24.2: Methyl
(S)-3-amino-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]propanoate
dihydrochloride
In a manner analogous to example 3.3, using 785 mg (1.9 mmol) of
methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(2-methylpropane-1-sulfonyl)piperazin-
-1-yl]propanoate, 621 mg (85%) of methyl
(S)-3-amino-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]propanoate
dihydrochloride are obtained in the form of a solid.
24.3: Methyl
(S)-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4-(2-methylquinol-
in-4-ylmethoxy)-benzenesulfonylamino]propanoate
In a manner analogous to example 3.6, using 621 mg (1.6 mmol) of
methyl
(S)-3-amino-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]propanoate
dihydrochloride and 876 mg (2.3 mmol) of
4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride
hydrochloride (prepared as described in example 17.2), 643 mg (64%)
of methyl
(S)-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4-(2-methylquinol-
in-4-ylmethoxy)benzenesulfonylamino]propanoate are obtained in the
form of an oil.
24.4:
(S)-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4-(2-methylq-
uinolin-4-ylmethoxy)benzenesulfonylamino]propanoic acid
In a manner analogous to example 3.7, using 643 mg (1.0 mmol) of
methyl
(S)-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4-(2-methylquinol-
in-4-ylmethoxy)benzenesulfonylamino]propanoate, 395 mg (63%) of
(S)-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4-(2-methylquinol-
in-4-ylmethoxy)benzenesulfonylamino]propanoic acid are obtained in
the form of a white solid.
24.5:
(S)--N-hydroxy-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4-
-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide
In a manner analogous to example 3.8, using 390 mg (0.6 mmol) of
(S)-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4-(2-methylquinol-
in-4-ylmethoxy)benzenesulfonylamino]propanoic acid, 12 mg (3%) of
(S)--N-hydroxy-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4-(2-m-
ethylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide are
obtained in the form of a white solid.
.sup.1H NMR (.delta., DMSO): 1.01 (d, J=6.7 Hz, 6H); 2.05 (m, 1H);
2.49 (m, 4H); 2.67 (s, 3H); 2.86 (d, J=6.6 Hz, 2H); 3.00-3.10 (m,
6H); 3.31 (m, 1H); 5.71 (s, 2H); 7.34 (d, J=8.9 Hz, 2H); 7.52 (m,
1H); 7.57 (m, 2H); 7.76-7.80 (m, 3H); 7.98 (d, J=8.2 Hz, 1H); 8.10
(m, 1H); 8.93 (s, 1H); 10.66 (s, 1H).
EXAMPLE 25
(S)--N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-trifluoromethyl-
-pyrazolo[1,5-a]pyridin-3-ylmethoxy)benzenesulfonylamino]propionamide
25.1: Ethyl
2-trifluoromethylpyrazolo[1,5-a]pyridine-3-carboxylate
A solution of 2.1 g (38 mmol) of KOH in 20 ml of water and then 6.7
g (30 mmol) of 1-aminopyridinium iodide are added to a solution of
2.5 g (15 mmol) of ethyl 4,4,4-trifluorobut-2-ynoate in 25 ml of
dichloromethane. After stirring at ambient temperature for 5 h,
water is added and the reaction medium is extracted with
dichloromethane. The organic phase is washed with water, dried over
magnesium sulfate. filtered and concentrated. The residue obtained
is purified by chromatography on silica gel, elution being carried
out with an 8/2 heptane/ethyl acetate mixture. 2.8 g (73%) of ethyl
2-trifluoromethylpyrazolo[1,5-a]pyridine-3-carboxylate are obtained
in the form of a yellow solid.
25.2:
(2-trifluoromethylpyrazolo[1,5-.alpha.]pyridin-3-yl)methanol
A solution of 2.8 g (11 mmol) of ethyl
2-trifluoromethylpyrazolo[1,5-.alpha.]pyridine-3-carboxylate in 50
ml of tetrahydrofuran is added dropwise to a suspension of 0.5 g
(12 mmol) of lithium aluminum hydride in 45 ml of tetrahydrofuran.
The reaction medium is then stirred at 70.degree. C. for 3 h. After
dropwise addition of 2.5 ml of methanol and then of 1.8 ml of an
aqueous solution of sodium hydroxide having a concentration of 2N,
the reaction medium is stirred for 20 min at ambient temperature
and then filtered. The filtrate is dried over magnesium sulfate,
filtered and concentrated under vacuum. 2.3 g (100%) of
(2-trifluoromethylpyrazolo[1,5-c]pyridin-3-yl)methanol are obtained
in the form of a solid.
25.3: Methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1-
,5-a]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoate
In a manner analogous to example 11.1, using 800 mg (1.9 mmol) of
methyl
(S)-3-(4-hydroxy-benzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl-
)propanoate (prepared as described in 5.1) and 540 mg (2.5 mmol) of
(2-trifluoromethylpyrazolo[1,5-o]pyridin-3-yl)methanol, 380 mg
(32%) of methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyr-
azolo[1,5-a]pyridin-3-yl-methoxy)benzenesulfonylamino]propanoate
are obtained in the form of a white solid.
25.4:
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyraz-
olo[1,5-.alpha.]pyridin-3-yl-methoxy)benzenesulfonylamino]propanoic
acid
In a manner analogous to example 3.7, using 380 mg (0.6 mmol) of
methyl
(S)-2-(4-methanesulfonyl-piperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[-
1,5-c]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoate, 237 mg
(64%) of
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1-
,5-.alpha.]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoic acid
are obtained in the form of a white solid.
25.5:
(S)--N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-trifluoro-
methylpyrazolo[1,5-.alpha.]pyridin-3-ylmethoxy)benzenesulfonylamino]propio-
namide
In a manner analogous to example 3.8, using 230 mg (0.4 mmol) of
(S)-2-(4-methanesulfonyl-piperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[-
1,5-a]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoic acid, 9 mg
(4%) of
(S)--N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-trifluorome-
thylpyrazolo[1,5-.alpha.]pyridin-3-ylmethoxy)benzene-sulfonylamino]propion-
amide are obtained in the form of a white solid.
.sup.1H NMR (.delta., DMSO): 2.51-2.54 (m, 4H); 2.84 (s, 3H); 2.95
(m, 1H); 2.97-3.04 (m, 4H); 3.10 (m, 1H); 3.32 (m, 1H); 5.45 (s,
2H); 7.20-7.25 (m, 3H); 7.49-7.51 (m, 2H); 7.76 (d, J=8.8 Hz, 2H);
8.04 (m, 1H); 8.87 (d, J=7 Hz, 2H); 8.90 (m, 1H).
EXAMPLE 26
(S)--N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2--
[4-(propane-2-sulfonyl)piperazin-1-yl]propionamide
26.1: Methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(propane-2-sulfonyl)piperazin-1-yl]pr-
opanoate
In a manner analogous to example 20.2, using 800 mg (2.8 mmol) of
methyl (S)-3-tert-butoxycarbonylamino-2-piperazin-1-ylpropanoate
(prepared as described in example 23.1) and 342 .mu.l (3.1 mmol) of
propane-2-sulfonyl chloride, 700 mg (64%) of methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(propane-2-sulfonyl)piperazin-1-yl]pr-
opanoate are obtained in the form of an oil.
26.2: Methyl
(S)-3-amino-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propanoate
dihydrochloride
In a manner analogous to example 3.3, using 700 mg (1.8 mmol) of
methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(propane-2-sulfonyl)piperazin-1-yl]pr-
opanoate, 620 mg (86%) of methyl
(S)-3-amino-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propanoate
dihydrochloride are obtained in the form of an oil.
26.3: Methyl
(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(propan-
e-2-sulfonyl)-piperazin-1-yl]propanoate
In a manner analogous to example 17.6, using 620 mg (1.5 mmol) of
methyl
(S)-3-amino-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propanoate
dihydrochloride and 830 mg (2.1 mmol) of
4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride
hydrochloride (prepared as described in the example 17.2), 505 mg
(54%) of methyl
(S)-3-[4-(2-methylquinolin-4-ylmeth-oxy)benzenesulfonylamino]-2-[4-(propa-
ne-2-sulfonyl)piperazin-1-yl]propanoate are obtained in the form of
a white solid.
26.4:
(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(p-
ropane-2-sulfonyl)-piperazin-1-yl]propanoic acid
In a manner analogous to example 3.7, using 505 mg (0.8 mmol) of
methyl
(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(propan-
e-2-sulfonyl)piperazin-1-yl]propanoate, 135 mg (27%) of
(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(propan-
e-2-sulfonyl)-piperazin-1-yl]propanoic acid are obtained in the
form of a white solid.
26.5:
(S)--N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylami-
no]-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propionamide
In a manner analogous to example 3.8, using 135 mg (0.2 mmol) of
(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(propan-
e-2-sulfonyl)piperazin-1-yl]propanoic acid, 24 mg (17%) of
(S)--N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-
-[4-(propane-2-sulfonyl)piperazin-1-yl]propionamide are obtained in
the form of a white solid.
.sup.1H NMR (.delta., DMSO): 1.19 (d, J=6.8 Hz, 6H); 2.45 (m, 4H);
2.68 (s, 3H); 2.80-2.90 (m, 1H); 2.95-3.15 (m, 6H); 3.29 (m, 1H);
5.72 (s, 2H); 7.34 (d, J=8.9 Hz, 2H); 7.52 (m, 1H); 7.57 (m, 2H);
7.76-7.80 (m, 3H); 7.98 (d, J=8.2 Hz, 1H); 8.10 (d, J=8.1 Hz, 1H);
8.93 (s, 1H); 10.66 (s, 1H).
EXAMPLE 27
(S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-trifluoromethylpyrazolo[1-
,5-a]pyridin-3-ylmethoxy)benzenesulfonylamino]propionamide
27.1: 4-Hydroxybenzenesulfonyl chloride
A solution of 7 g (30 mmol) of the sodium salt of
4-hydroxybenzenesulfonic acid dihydrate in 40 ml of
dimethylformamide is added dropwise to a solution of 15.5 ml (181
mmol) of oxalyl chloride in 120 ml of dichloromethane cooled to
-30.degree. C. The reaction medium is slowly brought back to
ambient temperature and then stirred at ambient temperature for 18
h. After the addition of 200 ml of ice, the reaction medium is
extracted with ethyl acetate. The organic phase is washed with
water and with a saturated aqueous solution of sodium chloride,
dried over magnesium sulfate, filtered and concentrated. 6.2 g
(100%) of 4-hydroxybenzenesulfonyl chloride are obtained in the
form of a colorless oil.
27.2: Methyl
(S)-2-(4-benzylpiperazin-1-yl)-3-(4-hydroxybenzenesulfonylamino)propanoat-
e
In a manner analogous to example 3.6, using 5.8 g (30 mmol) of
4-hydroxybenzenesulfonyl chloride and 7.7 g (20 mmol) of methyl
(S)-3-amino-2-(4-benzylpiperazin-1-yl)propanoate trihydrochloride
(prepared as described in example 17.5), 2.25 g (27%) of methyl
(S)-2-(4-benzylpiperazin-1-yl)-3-(4-hydroxybenzenesulfonylamino)propanoat-
e are obtained in the form of a white solid.
27.3: Methyl
(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-.alpha-
.]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoate
In a manner analogous to example 11.1, using 500 mg (1.1 mmol) of
methyl
(S)-2-(4-benzylpiperazin-1-yl)-3-(4-hydroxybenzenesulfonylamino)propanoat-
e and 370 mg (1.7 mmol) of
(2-trifluoro-methylpyrazolo[1,5-.alpha.]pyridin-3-yl)methanol
(prepared as described in example 25.2), 350 mg (50%) of methyl
(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-c]pyri-
din-3-ylmeth-oxy)benzenesulfonylamino]propanoate are obtained in
the form of a colorless oil.
27.4:
(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-a-
]pyridin-3-ylmeth-oxy)benzenesulfonylamino]propanoic acid
In a manner analogous to example 3.7, using 350 mg (0.5 mmol) of
methyl
(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-a]pyri-
din-3-ylmethoxy)benzenesulfonylamino]propanoate, 165 mg (48%) of
(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-a]pyri-
din-3-ylmethoxy)benzenesulfonylamino]propanoic acid are obtained in
the form of a white solid.
27.5:
(S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-trifluoromethylpyra-
zolo[1,5-.alpha.]pyridin-3-ylmethoxy)benzenesulfonylamino]propionamide
In a manner analogous to example 3.8, using 165 mg (0.3 mmol) of
(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-.alpha-
.]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoic acid, 50 mg
(29%) of
(S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-trifluoromethylpyrazolo[-
1,5-.alpha.]pyridin-3-ylmethoxy)benzenesulfonylamino]propionamide
are obtained in the form of a white solid with a melting point of
138.degree. C.
.sup.1H NMR (.delta., DMSO): 2.20 (m, 4H); 2.38 (m, 4H); 2.65-2.75
(m, 1H); 2.86-2.98 (m, 2H); 3.35 (m, 2H); 5.37 (s, 2H); 7.10-7.25
(m, 8H); 7.35-7.44 (m, 2H); 7.68 (d, J=8.9 Hz, 2H); 7.98 (d, J=9
Hz, 1H); 8.81 (m, 2H); 10.52 (s, 1H).
EXAMPLE 28
Enzymatic Assay for TACE Inhibition
Description of the Assay
The products are solubilized in DMSO at a concentration of 10 mM. A
serial 3-fold dilution over 10 points is carried out so as to have
a concentration range of from 10 .mu.M to 0.5 nM final
concentration.
The TACE enzyme is an internal production (carried out according to
the publication "protein Eng Des Sel 2006, 19, 155-161") and is
added so as to have a signal equivalent to 6 times the background
noise in 2 h at 37.degree. C. The reaction is carried out in 50 mM
Tris buffered medium containing 4% glycerol, pH 7.4. The
fluorescent substrate is
MCA-Pro-Leu-Ala-Val-(Dpa)-Arg-Ser-Ser-Arg-NH.sub.2 (R&D
systems, reference: ES003). The substrate is cleaved by the enzyme
between the alanine and the valine, thus releasing a fluorescent
peptide (excitation: 320 nm, emission: 420 nm). The substrate is
used at 40 .mu.M. The reaction is carried out in a final volume of
10 .mu.l (4 .mu.l inhibitor, 4 .mu.l substrate, 2 .mu.l enzyme) in
a low volume 384-well plate (Corning reference: 3676). The plate is
incubated at ambient temperature for 2 h, and then read by
fluorescence on a Pherastar reader (BMG labtech). The IC.sub.50 is
determined using mathematical processing software (XLfit).
Product Assay
TABLE-US-00002 Example No. % TACE inhibition at 10 .mu.M IC50 -
TACE (nM) ex1 100 87 ex2 100 32 ex4 95 497 ex5 99 21 ex6 99 52 ex8
100 127 ex9 100 147 ex10 93 47 ex11 93 24 ex13 96 108 ex14 98 64
ex16 96 168 ex17 91 62 ex18 90 67 ex19 92 41 ex21 97 63 ex23 97 53
ex24 98 86 ex26 98 33
On the basis of the results obtained in the TACE enzymatic assay
described above, the compounds claimed in the present invention are
TNF-alpha converting enzyme (TACE) inhibitors and consequently may
be potential active ingredients for the treatment of pathological
conditions for which reducing TNF-alpha production would be of
great interest.
EXAMPLE 29
Selectivity Assay
Principle of the Assay:
The molecules are dose-response tested on the following enzymes:
MMP1, MMP3, MMP9, ADAM9 and ADAM10, according to the same protocol
as that described for the TACE enzyme in example 28, but with
different substrates (MMP R&D systems, reference: P126-990, and
ADAM R&D systems, reference: ES003).
The enzymes are purchased from Calbiochem.
Product Assay:
TABLE-US-00003 IC50 (nM) Example MMP1 MMP3 MMP9 ADAM9 ADAM10 TACE 5
5100 3200 >10000 >10000 >10000 21 18 670 849 >10000
9254 >10000 67 19 2303 1770 >10000 3054 >10000 41 20 3935
4775 >10000 >10000 >10000 140 21 1166 887 >10000
>10000 >10000 63 23 2221 1065 >10000 >10000 >10000
53 24 2059 1878 >10000 >10000 >10000 86 26 969 574
>10000 >10000 >10000 16 Apratastat 145 10 82 85 71 5
On the basis of the results obtained in the selectivity assay
described above, these compounds are also very selective for TACE
compared with the other ADAMs and MMPs, i.e. they have IC.sub.50
values for other ADAMs or MMPs that are at least 10 times higher
than that obtained for TACE, and more advantageously at least 100
times higher.
As it happens, insofar as it is known that the nonselective
inhibition of these families of enzymes induces adverse side
effects observed in vivo, the selective inhibition of TACE compared
with these other enzymes should make it possible to reduce adverse
side effects when these molecules are administered for the
treatment of pathological conditions for which reducing TNF-alpha
production would be of great interest.
* * * * *
References